Method for magnetic modulation of neural conduction

ABSTRACT

Methods and related systems for modulating neural activity by repetitively blocking conduction in peripheral neural structures with magnetic stimuli are disclosed. Methods and systems for reversing effects of blocking stimuli and/or for producing substantially permanent conduction block are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing date(s) from the following listedapplication(s) (the “Related Applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related Application(s)).

RELATED APPLICATIONS

-   -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 11/999,721, titled “METHOD AND        SYSTEM FOR CYCLICAL NEURAL MODULATION BASED ON ACTIVITY STATE”,        naming RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, COLIN P.        DERDEYN, JOSHUA L. DOWLING, ELEANOR V. GOODALL, RODERICK A.        HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT,        NATHAN P. MYHRVOLD, MICHAEL A. SMITH, LOWELL L. WOOD, JR.,        VICTORIA Y. H. WOOD, AND GREGORY J. ZIPFEL as inventors, filed 5        Dec. 2007, which is currently co-pending, or is an application        of which a currently co-pending application is entitled to the        benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/070,361, filed Feb. 15, 2008        titled “METHOD FOR ELECTRICAL MODULATION OF NEURAL CONDUCTION”,        naming RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, COLIN P.        DERDEYN, JOSHUA L. DOWLING, ELEANOR V. GOODALL, RODERICK A.        HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT,        NATHAN P. MYHRVOLD, MICHAEL A. SMITH, LOWELL L. WOOD, JR.,        VICTORIA Y. H. WOOD, AND GREGORY J. ZIPFEL as inventors, filed        substantially contemporaneously herewith, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/070,331, filed Feb. 15, 2008        titled “SYSTEM FOR ELECTRICAL MODULATION OF NEURAL CONDUCTION”,        naming RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, COLIN P.        DERDEYN, JOSHUA L. DOWLING, ELEANOR V. GOODALL, RODERICK A.        HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT,        NATHAN P. MYHRVOLD, MICHAEL A. SMITH, LOWELL L. WOOD, JR.,        VICTORIA Y. H. WOOD, AND GREGORY J. ZIPFEL as inventors, filed        substantially contemporaneously herewith, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of U.S.        patent application Ser. No. 12/070,369, filed Feb. 15, 2008        titled “SYSTEM FOR MAGNETIC MODULATION OF NEURAL CONDUCTION”,        naming RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, COLIN P.        DERDEYN, JOSHUA L. DOWLING, ELEANOR V. GOODALL, RODERICK A.        HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT,        NATHAN P. MYHRVOLD, MICHAEL A. SMITH, LOWELL L. WOOD, JR.,        VICTORIA Y. H. WOOD, AND GREGORY J. ZIPFEL as inventors, filed        substantially contemporaneously herewith, which is currently        co-pending, or is an application of which a currently co-pending        application is entitled to the benefit of the filing date.

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation or continuation-in-part. Stephen G. Kunin, Benefit ofPrior-Filed Application, USPTO Official Gazette Mar. 18, 2003, availableat http://www.uspto.gov/web/offices/com/sol/og/2003/week11/patbene.htm.The present Applicant Entity (hereinafter “Applicant”) has providedabove a specific reference to the application(s) from which priority isbeing claimed as recited by statute. Applicant understands that thestatute is unambiguous in its specific reference language and does notrequire either a serial number or any characterization, such as“continuation” or “continuation-in-part,” for claiming priority to U.S.patent applications. Notwithstanding the foregoing, Applicantunderstands that the USPTO's computer programs have certain data entryrequirements, and hence Applicant is designating the present applicationas a continuation-in-part of its parent applications as set forth above,but expressly points out that such designations are not to be construedin any way as any type of commentary and/or admission as to whether ornot the present application contains any new matter in addition to thematter of its parent application(s).

All subject matter of the Related Applications and of any and allparent, grandparent, great-grandparent, etc. applications of the RelatedApplications is incorporated herein by reference to the extent suchsubject matter is not inconsistent herewith.

SUMMARY

In one aspect, a method of modulating neural activity may include thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject with a magnetic field while the subject is in afirst activity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate, and repeating the steps of producing a reversible conductionblock in a peripheral neural structure of a subject with a magneticfield while the subject is in a first activity state and reversing thereversible conduction block in the peripheral neural structure of thesubject to permit conduction in the peripheral neural structure when thesubject is in a second activity state.

In another aspect, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a magnetic field while the subject is in a firstactivity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate by applying a reversing stimulus configured to counter theblocking stimulus used to produce the reversible conduction block in theperipheral neural structure of the subject, and repeating the steps ofproducing a reversible conduction block in a peripheral neural structureof a subject while the subject is in a first activity state andreversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state.

In yet another aspect, a method of modulating neural activity mayinclude producing a reversible conduction block in a peripheral neuralstructure of a subject with a magnetic field while the subject is in afirst activity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate, repeating the steps of producing a reversible conduction block ina peripheral neural structure of a subject with a magnetic field whilethe subject is in a first activity state and reversing the reversibleconduction block in the peripheral neural structure of the subject topermit conduction in the peripheral neural structure when the subject isin a second activity state, determining that producing the reversibleconduction block in the peripheral neural structure of the subject witha magnetic field while the subject is in a first activity state resultsin a desired effect in the subject, and producing a non-reversibleconduction block in the peripheral neural structure of the subject.

In still another aspect, a method of modulating neural activity mayinclude producing a reversible conduction block of a subset of nervefibers in a peripheral neural structure of a subject with a magneticfield while the subject is in a first activity state, reversing thereversible conduction block of the subset of nerve fibers in theperipheral neural structure of the subject to permit conduction in thesubset of nerve fibers in the peripheral neural structure when thesubject is in a second activity state, and repeating the steps ofproducing a reversible conduction block in the subset of nerve fibers ina peripheral neural structure of a subject with a magnetic field whilethe subject is in a first activity state and reversing the reversibleconduction block in the subset of nerve fibers in the peripheral neuralstructure of the subject to permit conduction in the subset of nervefibers in the peripheral neural structure when the subject is in asecond activity state.

In addition to the foregoing, other method aspects are as described inthe claims, drawings, and text forming a part of the present disclosure.

In one aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure; a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure and generate a blocking stimulus controlsignal for driving production of a magnetic field blocking stimulusconfigured to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate; and a blocking stimulus source configured to produce a magneticfield blocking stimulus responsive to the blocking stimulus controlsignal.

In another aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure; a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure and generate a blocking stimulus controlsignal for driving production of a magnetic field blocking stimulusconfigured to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, and a blocking stimulus source configured to be worn on the bodyof the subject and to produce a magnetic field blocking stimulusresponsive to the blocking stimulus control signal.

In still another aspect, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure; a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure and generate a blocking stimuluscontrol signal for driving production of a magnetic field blockingstimulus configured to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state; and a blocking stimulus source configured to bepositioned beneath at least a portion of the body of the subject and toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal.

In a further aspect, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure; a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure and generate a blocking stimuluscontrol signal for driving production of a magnetic field blockingstimulus configured to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state; and a blocking stimulus source configured to beimplanted within the body of the subject and to produce a magnetic fieldblocking stimulus responsive to the blocking stimulus control signal.

In still another aspect, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure; a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure, generate a blocking stimuluscontrol signal for driving production of a magnetic field blockingstimulus configured to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state; and generate a release stimulus control signal forcontrolling discontinuation of production of the magnetic field blockingstimulus when the subject is in the second activity state; a sensoroperatively connected to the signal input structure and configured togenerate the signal indicative of an activity state of at least aportion of a body of a subject innervated by a peripheral neuralstructure responsive to an activity of the at least a portion of thebody of the subject; and a blocking stimulus source configured toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal.

In another aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure; a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure, generate a blocking stimulus controlsignal for driving production of a magnetic field blocking stimulusconfigured to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, and generate a reversing stimulus control signal for drivingproduction of a reversing stimulus to counter the magnetic fieldblocking stimulus used to produce the reversible conduction block in theperipheral neural structure of the subject; a blocking stimulus sourceconfigured to produce a magnetic field blocking stimulus responsive tothe blocking stimulus control signal; and a reversing stimulus sourceconfigured to produce a reversing stimulus responsive to the reversingstimulus control signal.

In another aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure; a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure, generate a blocking stimulus controlsignal for driving production of a magnetic field blocking stimulusconfigured to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, determine that producing the reversible conduction block in theperipheral neural structure of the subject while the subject is in afirst activity state results in a desired effect in the subject, andgenerate a non-reversible blocking source control signal for driving anon-reversible blocking source to perform an action adapted forproducing a non-reversible conduction block in the peripheral neuralstructure of the subject; a blocking stimulus source configured toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal; and a non-reversible blocking source configuredto perform an action adapted for producing a non-reversible conductionblock in the peripheral neural structure of the subject responsive tothe non-reversible blocking source control signal.

In addition to the foregoing, other system aspects are described in theclaims, drawings, and text forming a part of the present disclosure.

In one or more various aspects, related systems include but are notlimited to circuitry and/or programming, including instructions carriedon signal bearing media, for effecting the herein-referenced methodaspects.

The foregoing is a summary and thus may contain simplifications,generalizations, inclusions, and/or omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is NOT intended to be in any way limiting. Inaddition to the illustrative aspects, embodiments, and featuresdescribed above, further aspects, embodiments, and features will becomeapparent by reference to the drawings and the following detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is an illustration of conduction in a single nerve fiber;

FIG. 1B is an illustration of conduction block in the single nerve fiberdepicted in FIG. 1A;

FIG. 2A is an illustration of conduction in nerve;

FIG. 2B is a cross-sectional view of the nerve depicted in FIG. 2A;

FIG. 2C is an illustration of the effect of a complete conduction blockin the nerve depicted in FIG. 2A;

FIG. 2D is a cross-sectional view of the nerve depicted in FIG. 2C;

FIG. 2E is an illustration of the effect of a partial conduction blockin the nerve depicted in FIG. 2A;

FIG. 2F is a cross-sectional view of the nerve depicted in FIG. 2E;

FIG. 3 is a schematic diagram of a system for producing conduction blockin a peripheral neural structure;

FIG. 4 is a flow diagram of method of modulating neural activity;

FIG. 5 is an illustration of application patterns for blocking stimuli;

FIG. 6 is a flow diagram of method of modulating neural activity;

FIG. 7 is a flow diagram of method of modulating neural activity;

FIG. 8 is an illustration of an embodiment of a system in which ablocking stimulus source is located in an arm band;

FIG. 9 is an illustration of types of blocking stimuli;

FIG. 10 is an illustration of an embodiment of a system in which ablocking stimulus source is located in chair;

FIG. 11 is an illustration of an embodiment of a system in which ablocking stimulus source is located in a bed;

FIG. 12 is an illustration of an embodiment of a system in which ablocking stimulus source is implanted within the body of a subject;

FIG. 13 is a flow diagram of a method of modulating neural activity;

FIG. 14 is a flow diagram of a method of modulating neural activity;

FIG. 15 is an illustration of an embodiment of a neural modulationsystem with a reversing stimulus source;

FIG. 16 is a flow diagram of a method of modulating neural activity;

FIG. 17 is a flow diagram of a method of modulating neural activity;

FIG. 18 is an illustration of an embodiment of a neural modulationsystem with a non-reversible blocking source;

FIG. 19 is a flow diagram of a method of modulating neural activity;

FIGS. 20A-20D depicts examples of magnetic field sources;

FIG. 21 is a block diagram of an example of a neural modulation system;

FIG. 22 is a block diagram of an example of a neural modulation system;

FIG. 23 is a block diagram of another example of a neural modulationsystem;

FIG. 24 is a block diagram of a further example of a neural modulationsystem;

FIG. 25 is a block diagram of a further example of a neural modulationsystem;

FIG. 26 is a block diagram of another example of a neural modulationsystem; and

FIG. 27 is a block diagram of a signal processing portion of a neuralmodulation system.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

Although the following terms are known in the art, they are generallydefined below for the convenience of the reader:

DEFINITIONS

Central Nervous System (CNS)—the brain, spinal cord, optic nerves andretina.

Peripheral Nervous System (PNS)—all the nerves in the body that lieoutside of the brain and spinal cord, i.e., the cranial nerves, spinalnerves, nerve plexuses, and their associated spinal and autonomicganglia.

Autonomic Nervous System (ANS)—the portion of the nervous system thatregulates involuntary body functions, including heart and circulation,respiration, digestion, temperature regulation, etc. The Autonomicnervous system includes two divisions, the sympathetic nervous systemand the parasympathetic nervous system.

Sympathetic nervous system—the division of the autonomic nervous system,which, broadly speaking, functions to mobilize the body's energy andresources during times of stress and arousal to prepare for “fight orflight”, e.g., it accelerates heart rate, constricts blood vessels,elevates blood pressure, etc.

Parasympathetic nervous system—the division of the autonomic nervoussystem that regulates body functions during relaxed states.

Neuron—a nerve cell, the basic functional unit of the nervous system. Aneuron typically includes a cell body, and one or more processes calledaxons and dendrites.

Axon—An axon is a long slender process of a nerve cell that conductselectrical impulses away from the cell body.

Action Potential—a brief, regenerative change in membrane potential thatpropagates actively along membrane of neuron or other excitable cells.

Dendrite—A dendrite is a process of a nerve cell that conductselectrical impulses toward the cell body. Often, a neuron may havemultiple, relatively short dendrites.

Nerve Fiber—The term “nerve fiber” may be used in connection withperipheral neurons to describe long slender processes (either axons ordendrites) that may conduct electrical impulses away from or toward thecell body.

Nerve—a cable-like bundle of multiple nerve fibers, capable of carryingsignals between the central nervous system and other organs and tissuesof the body. Cranial nerves may connect directly to parts of the brain.

Fascicle—a bundle of nerve fibers within a nerve. Each fascicle issurrounded by a dense sheath of tissue called perineurium, while a groupof fascicles that make up a nerve are surrounded and held together bylooser connective tissue called epineurium.

Nerve Plexus—a region of crossover and regrouping of nerve fibers frommultiple nerves.

Ganglion—in the peripheral nervous system, a cluster of nerve cellbodies; sensory (afferent) ganglia lie along spinal column on the dorsalroots. Autonomic ganglia (containing the cell bodies of autonomicneurons) may lie parallel to the spinal column or in or near theirtarget organs.

Spinal Root—root portion of spinal nerve, as it branches off of spinalcord and passes through bony canal through vertebra.

Methods and systems for modulating neural activity by producingconduction block in peripheral neural structures in a controlled fashionare disclosed herein. Effects of peripheral nerve block depend at leastin part on the type of nerve or nerve fibers blocked and the targetorgan or tissue innervated by the blocked nerve or nerve fibers. It isbelieved that delivery of blocking stimuli to coincide at least in partwith particular activity states in a subject may allow desired effectsof blocking (e.g., modulation of immune or inflammatory response,decrease in pain, etc.) to be produced while limiting inconvenience,discomfort, and/or other undesired effects (numbness, diminished oraltered sensation, decreased muscle force or control, interference withautonomic functions), or for other reasons. For example, blockingstimuli may be delivered during periods of reduced activity of thesubject (including, but not limited to, physical activity, physiologicalactivity, or other measures of activity, in all or a portion of the bodyof the subject). Effects of peripheral nerve block depend at least inpart on the type of nerve or nerve fibers blocked and the target organor tissue innervated by the blocked nerve or nerve fibers.

By way of background, FIGS. 1A and 1B provide a conceptual illustrationof the blocking of conduction of an action potential along a singlenerve fiber. FIG. 1A depicts conduction of action potentials (referredto collectively as “neural activity”) in a single nerve fiber 10 (anelongated nerve process, or axon or dendrite) when no conduction blockis present. Neural activity may be sensed from nerve fiber 10 with, forexample, an electrode 12 located at a first position 14 on nerve fiber10. Sensed neural activity may be represented by trace 16, whichincludes action potentials 18 a, 18 b, 18 c and 18 d occurring at timest_(a), t_(b), t_(c) and t_(d). The direction of conduction of actionpotentials along nerve fiber 10 is indicated by the arrow. Trace 20,which may be sensed with electrode 22 at a second position 24 located ata distance l from first position 14 on nerve fiber 10, includes actionpotentials 18 a, 18 b, 18 c and 18 d occurring at times t_(a)+t_(cd),t_(b)+t_(cd), t_(c)+t_(cd) and t_(d)+t_(cd), where t_(cd) is theconduction delay time, or the time for the action potentials to conductdown nerve fiber 10 from first position 14 to second position 24.Conduction delay time t_(cd) is equal to l/v, where l is the distancebetween first position 14 and second position 24 and v is the conductionvelocity.

FIG. 1B depicts the effect of a conduction block in nerve fiber 10,indicated by cross-hatching in blocked region 30. When conduction isblocked at region 30, action potentials 28 e, 28 f, 28 g and 28 h,occurring at times t_(e), t_(f), t_(g) and t_(h) in trace 26 may besensed with electrode 12 at first position 14. However, conduction ofthe action potentials in the direction indicated by the arrow is blockedso they cannot travel past region 30 to second position 24. Accordingly,trace 32, which may be sensed with electrode 22 at second position 24,will not contain any action potentials.

FIGS. 2A-2F illustrate the effects of complete and partial conductionblock on a nerve made up of multiple nerve fibers. A nerve 50 is shownin longitudinal section in FIG. 2A, and in cross section (taken atsection line 2B-2B) in FIG. 2B. Nerve 50 contains multiple nerve fibers54. An electrode 56 at first position 58 may record a compound signal 60from nerve 50. Compound signal 60 is made up of the summation of actionpotentials produced by multiple individual nerve fibers (e.g., as may beproduced in response to an electrical stimulus or other stimulus thatactivates multiple nerve fibers at substantially the same time). If thedirection of conduction is as indicated by the arrow, an electrode 62 atsecond position 64 may record compound signal 66. Because actionpotentials on individual nerve fibers may travel at different conductionvelocities, action potentials that sum to form compound signal 60 atfirst position 58 may not arrive at second position 64 at the samedelays relative to each other. Accordingly, compound signal 66 mayrepresent the summation of the same action potentials that made upcompound signal 60, but because they arrive at second position 64 atdifferent relative delays, compound signal 66 may have a different shapethan compound signal 60.

FIG. 2C depicts nerve 50 in longitudinal section, with a completeconduction block in region 70, as indicated by cross-hatching.Conduction block is indicated in region 74 in the cross-section of thesame nerve, taken at section line 2D-2D and shown in FIG. 2D. Compoundsignal 75 sensed at first position 58 is unchanged relative to compoundsignal 60 shown in FIG. 1A, but compound signal 76, sensed at secondposition 64 with electrode 62, includes no activity, because conductionof action potentials was blocked in all fibers at the blocked region asindicated at 70 and 74.

FIG. 2E depicts in longitudinal view nerve 50 with a partial conductionblock, with blocked fibers in area 80, as indicated by cross-hatching.Conduction block is indicated by area 84 in the cross-section shown inFIG. 2F, taken along section line 2F-2F in FIG. 2E. Compound signal 85sensed at first position 58 is unchanged relative to compound signal 60as shown in FIG. 2A, but compound signal 86, sensed at second position64 with electrode 62, is of lower amplitude because conduction of actionpotentials was blocked in the subset of fibers passing through theblocked region as indicated at areas 80 and 84. Accordingly, compoundsignal 86 is formed by the summation of action potentials from thosefibers lying outside of area 80, i.e. fibers lying within region 88 incross-section of FIG. 2F. As seen in the cross-section of FIG. 2F, whena partial conduction block is produced in a nerve, a subset of the nervefibers (lying within area 84) may be blocked, and another subset of thenerve fibers (lying within region 88) may conduct as usual. In theexample shown in FIG. 2F, the blocked subset of nerve fibers fallswithin a particular spatial distribution. In some cases, a subset ofnerve fibers within a nerve may be blocked based on fiber diameter,fiber type, presence of a biomarker, or other parameter instead of or inaddition to the location of the nerve fiber with the nerve.

Conduction block in peripheral nerves may be produced by application ofappropriately configured magnetic stimuli as described elsewhere herein,or by various other approaches as known to those of skill in the art.For example, commonly owned U.S. patent application Ser. No. 11/999,721,titled “METHOD AND SYSTEM FOR CYCLICAL NEURAL MODULATION BASED ONACTIVITY” filed 5 Dec. 2007, and listing as inventors Ralph Dacey, Jr.,Gregory J. Della Rocca, Colin P. Derdeyn, Joshua Dowling, Eleanor V.Goodall, Rod Hyde, Muriel Y. Ishikawa, Jordin Kare, Eric Leuthardt,Nathan Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Wood,Gregory Zipfel, which is incorporated herein by reference in itsentirety, describes various approaches for blocking conduction inperipheral neural structures.

FIG. 3 is a schematic diagram illustrating a neural modulation system100 for modulating neural activity by blocking conduction in at least aportion of a peripheral neural structure 140. A body portion of asubject is indicated generally at 120, including skin surface 130overlying peripheral neural structure 140 (in this example, a peripheralnerve) and surrounding tissue 150. Neural modulation system 100 includesblocking stimulus source 160, which is capable of generating magneticfield blocking stimulus 170 to block conduction in region 180 ofperipheral neural structure 140 (in this example, a peripheral nerve).The neural modulation system 100 includes a signal input structure 192configured to receive a signal 194 indicative of an activity state of atleast a portion 120 of a body of a subject innervated by a peripheralneural structure, a signal processing portion configured to distinguisha first activity state of the at least a portion 120 of the body of thesubject innervated by the peripheral neural structure 140 from a secondactivity state of the at least a portion 120 of the body of the subjectinnervated by the peripheral neural structure from the signal 194received at the signal input structure 192 and generate a blockingstimulus control signal 196 for driving production of a magnetic fieldblocking stimulus 170. Magnetic field blocking stimulus 170 may beconfigured to reversibly block conduction in the peripheral neuralstructure 140 of the subject during at least a portion of the firstactivity state; blocking stimulus source 160 may be configured toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal 196. Sensor 190 may sense at least one parameterindicative of an activity state in the subject, which may be an overallactivity level of the subject, or a level of use or activity of a bodyportion innervated by peripheral neural structure 140. A signal 194 fromsensor 190 may be connected to signal input structure 192 of signalprocessing portion 110.

The term “activity state” refers to one of at least two possiblecategories of activity that are characterized by and distinguishablefrom each other by one or more quantifiable parameters. Activity mayrefer to overall activity of the subject or use or activity of a bodyportion innervated by the peripheral neural structure. Activity mayinclude or be reflected by physical activity, physiological activity, orother measures or indicators of activity, as described in greater detailelsewhere herein.

For purposes of methods as disclosed herein, at least two activitystates may be defined, with appropriate values or value ranges of theone or more quantifiable parameters associated therewith. The differentactivity states may differ with regard to the level of activity, or, insome cases, the nature of the activity. In some cases, the overallactivity of the subject may be lower in the first activity state than inthe second activity state. For example, the first activity state may bea “sleep state” and the second activity state may be a “waking state.”Alternatively, the first activity state may be a “resting,” “lying down”or “sitting” activity state while the second activity state may be a“moving about,” “standing” or “walking” activity state.

The activity or use of a specific portion of the subject's body, ratherthan the overall activity of the subject, may be of interest. Forexample, the first and second activity states may be defined such thatthe use of a body portion innervated by the peripheral neural structureby the subject is lower in the first activity state than in the secondactivity state. If the body portion innervated by the peripheral neuralstructure is the subject's arm, a low use state may be obtained when thearm is resting in the subject's lap, on an arm rest or table top, or ina sling, while the subject stands or walks. Low use or activity of thesubject's arm may also be obtained while the overall activity of thesubject is low, e.g. the subject is lying down or sleeping. Conversely,a moderate or high use or activity state of a body portion, e.g., thesubject's arm, may be obtained while the subject's overall activitylevel is either high or low. For example, the subject could use the armfor writing, typing, holding a book, knitting, etc. while sittingquietly with a low overall activity level. A subject may also have ahigh use or activity state of, e.g., an arm in combination with anoverall high activity level.

FIG. 4 illustrates a method of modulating neural activity that may becarried out, for example, using the system depicted in FIG. 3. Themethod shown in FIG. 4 includes the steps of producing a reversibleconduction block in a peripheral neural structure of a subject with amagnetic field while the subject is in a first activity state (step200), reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 202), andrepeating the steps of producing a reversible conduction block in aperipheral neural structure of a subject with a magnetic field while thesubject is in a first activity state and reversing the reversibleconduction block in the peripheral neural structure of the subject topermit conduction in the peripheral neural structure when the subject isin a second activity state (step 204).

The method of modulating neural activity as shown generally in FIG. 4includes producing a reversible conduction block in a peripheral neuralstructure of a subject, which may be, for example, a peripheral nerve, aspinal root, an autonomic ganglion, or a nerve plexus. A peripheralnerve may be a sensory and/or motor nerve, an autonomic nerve (includingsympathetic and/or parasympathetic nerve, or a mixture of sensory,motor, sensory-motor, and/or autonomic nerve fibers). Examples ofspecific nerves that may be subject to reversible conduction blockinclude the radial nerve, median nerve, ulnar nerve, femoral nerve,obturator nerve, sciatic nerve, popliteal nerve, tibial nerve, peronealnerve, and vagus nerve. The geniculate ganglion is an example of aspecific ganglion that may blocked reversibly.

In the practice of the method outlined in FIG. 4, the first activitystate and the second activity state may be defined in several differentways, depending upon the intended application of the method. In somecases, as discussed previously, the first and second activity states mayrepresent first and second overall activity states of the subject, andin other cases, the use of a body portion innervated by the peripheralneural structure may be of interest, and the first and second activitystates may represent first and second states of use of the innervatedbody portion.

FIG. 5 illustrates a sensed activity, represented by trace 250; activitystate as determined from sensed activity, represented by trace 252; andseveral examples of blocking stimulus application patterns, which may beapplied responsive to the sensed activity, represented by traces 254,256 and 258. Time is indicated on the x-axis. Methods for deliveringblocking stimuli responsive to and/or relative to sensed activity isdescribed in greater detail in commonly owned U.S. patent applicationSer. No. 11/999,721, which, as noted elsewhere herein, is incorporatedherein by reference in its entirety. Trace 250 is an illustration of asensed activity of the type that might be detected from a subject over aperiod of time. Trace 250 does not represent any specific type of signal(it could be, for example, a physiological signal such as a heart rateor respiration rate, or a physical signal such as motion detection orpressure signal). In this example, the activity in the subject isclassified into one of two possible activity states, a first activitystate and a second activity state, and it is assumed that higher valuesof the signal indicate that the subject is more active and lower valuesof the signal indicate that the subject is less active. By setting anappropriate threshold value, as indicated at 260, it may be possible todistinguish between the first activity state (during which the value oftrace 250 is above the threshold value 260 and the second activity state(during which the value of trace 250 is below the threshold value 260).Trace 252 may be an overall activity state (which might be determinedfrom heart rate, for example) or an activity or use state of a portionof the body of the subject (which might be determined from activity of aparticular muscle, for example).

Examples of several representative patterns for application of blockingstimuli are also illustrated in FIG. 5. Trace 254 depicts a blockingstimulus pattern that corresponds directly to the activity state, withblocking stimulus applied (“on”) while the subject is in the firstactivity state and the blocking stimulus removed (“off”) while thesubject is in the second activity state. The blocking stimulus patternrepresented by trace 254 includes multiple blocking periods 270, 272,274 and 276, during which a blocking stimulus sufficient to produce areversible conduction block of at least a portion of the peripheralneural structure of the subject is applied, separated by release periods270, 272, 274 and 276 during which the blocking stimulus is reversed.Blocking periods 270, 272, 274 and 276 coincide with a first activitystate in the subject and release periods 270, 272, 274 and 276 coincideat least in part with a second activity state in the subject.

Trace 256 depicts a blocking stimulus pattern in which a blockingstimulus is applied at the onset of the first activity state and removedafter a time t_(a) after the onset of the first activity state. Trace258 depicts a blocking stimulus pattern in which a blocking stimulus isapplied at a time t_(b) after the onset of the first activity state andremoved at a time t_(c) after was applied. In this example, the periodduring which the blocking stimulus is applied or “on” may extend intothe second activity state in the subject. Trace 252 indicates theactivity state of the subject as thus determined.

In some applications, the steps of producing a reversible conductionblock in a peripheral neural structure of a subject while the subject isin a first activity state and reversing the reversible conduction blockin the peripheral neural structure of the subject to permit conductionin the peripheral neural structure when the subject is in a secondactivity state may occur over a period of time sufficient to produce amodulation of an immune response in a region innervated by theperipheral neural structure.

In some applications, the steps of producing a reversible conductionblock in a peripheral neural structure of a subject while the subject isin a first activity state and reversing the reversible conduction blockin the peripheral neural structure of the subject to permit conductionin the peripheral neural structure when the subject is in a secondactivity state occur over a period of time sufficient to produce amodulation of an inflammatory response in a region innervated by theperipheral neural structure.

A blocking stimulus may be delivered intermittently responsive toactivity state (for example according to a pattern as depicted in FIG.5) until a desired modulation of an immune or inflammatory response isobtained. Modulation of an inflammatory or immune response may beproduced using a method or system as described herein, and may involvethe provision of total or partial blocking stimulus to a sensory nerveinnervating a limb, join, or digit, to produce an effect e.g. asdescribed in Kane et al., “Protective effect of sensory denervation ininflammatory arthritis (evidence of regulatory neuroimmune pathways inthe arthritic joint),” Ann Rheum Dis 2005; 64:325-327. doi:10.1136/ard.2004.022277, or as described in Razavi et al., “TRPV1+sensory neurons control β cell stress and islet inflammation inautoimmune diabetes,” (showing elimination of activity from sensoryneurons innervating the pancreas may prevent development of diabetes);Cell; Dec. 15, 2006; pp. 1123-1135; Vol. 127, each of which isincorporated herein by reference in its entirety

The amount of time needed to produce modulation of an immune response orinflammatory response may be determined prior to use of the method,based on experimental or clinical data, or the method may be carried outuntil an appropriate modulation of immune or inflammatory response isobtained as determined by measurement of indicators of immune orinflammatory response, as known to those of skill in the art. Forexample, inflammation may be indicated by one or more of swelling,color, temperature, or pain or tenderness, and these parameters may bedetermined qualitatively or quantitatively, as described in U.S. Pat.No. 7,226,426, which is incorporated herein by reference in itsentirety. Inflammation may also be indicated by the presence ofT-lymphocytes or macrophages, which may be detectedimmunohistochemically, for example as described in Rooney, T.;Bresnihan, B.; Andersson, U.; Gogarty, M.; Kraan, M.; Schumacker, H. R.;Ulfgren, A.-K.; Veale, D. J.; Youssef, P. P.; and Tak, P. P;“Microscopic measurement of inflammation in synovial tissue:inter-observer agreement for manual quantitative, semiquantitative andcomputerized digital image analysis”; Ann. Rheumatic Disease; 2007; Vol.66, pp. 1656-1660; doi:10.1136/ard.2006.0611430; by eosinophils,cytokines, chemokines, and/or leukotrienes, as described in Howarth, P.H.; Persson, C. G. A.; Meltzer, E. O.; Jacobson, M. R.; Durhan, S. R.;and Silkoff, P. E.; “Objective monitoring of nasal airway inflammationin rhinitis”; J. Allergy Clin. Immunol.; 2005; Vol. 115; pp. S414-S441;and by other biomarkers, such as certain 14-3-3 proteins, as describedin Kilani, R. T.; Maksymowych, W. P.; Aitken, A.; Boire, G.; St. Pierre,Y.; Li, Y.; and Ghahary, A.; “Detection of high levels of 2 specificisoforms of 14-3-3 proteins in synovial fluid from patients with joininflammation”; J. Rheumatology; 2007; Vol. 34, No. 8; pp. 1650-1657;each of which is incorporated herein by reference in its entirety.Inflammation may also be indicated by products of tissue degradation,and/or immune response may be indicated by one or more of antibodies,immune cells, or chemical markers of immune response or inflammation, asdescribed in Poole, A. R.; “Immunochemical markers of jointinflammation, skeletal damage and repair: where are we now?”; Annals ofRheumatic Disease; 1994; Vol. 53; pp. 3-5; doi:10.1136/ard.53.1.3, whichis incorporated herein by reference in its entirety.

The amount of time needed to produce modulation of an immune response orinflammatory response will depend upon a number of factors, includingparameters of the blocking stimulus, the peripheral neural structure inwhich conduction block is produced, and the nature of the immune orinflammatory response of concern and the level of modulation that is tobe produced.

FIG. 6 illustrates variants of the method shown generally in FIG. 4. Themethod of FIG. 6 includes the steps of producing a reversible conductionblock in a peripheral neural structure of a subject with a magneticfield while the subject is in a first activity state (step 310),reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 312),receiving an input indicative of an activity state of the subject,wherein the input is indicative of at least one of a first activitystate and a second activity state of the subject (314) and repeating thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject with a magnetic field while the subject is in afirst activity state and reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate (step 316). In some embodiments, the method may include receivingan input representing physiological activity of the subject, asindicated at 318, which may include, for example, receiving an inputrepresenting the heart rate (as indicated at 320), respiration of thesubject (as indicated at 322), brain activity (as indicated at 324),peripheral neural (as indicated at 326), muscle activity (as indicatedat 328), or body temperature of the subject (as indicated at 330).Methods and devices for sensing these and other physiological signals orparameters are well known to those of skill in the art.

A physiological sensor as used in the method of FIG. 6 may be configuredto generate a signal indicative of activity of the heart of the subject,activity of brain of the subject, activity of a peripheral neural systemof the subject, activity of a muscle of the subject, respiration of thesubject, body temperature of the subject, or other physiological signalsthat may be indicative of an activity state of all or a portion of thebody of the subject. The detection of these and other physiologicalsignals is known to those of skill in the art. Examples of some possiblephysiological signals that may indicate activity of all or a portion ofa body of a subject include electroencephalographic signals (EEG),electromyographic signals (EMG), electrocardiographic signals (ECG),heart rate, blood pressure, blood oxygenation, respiration rate,respiratory volume, or body temperature. Receiving an input indicativeof an activity state of the subject may include receiving an inputrepresenting a rest or waking state of the subject; for example, rest orwaking state of a subject may be determined based on physiologicalparameters (EEG, heart rate, respiration rate, etc.). Specific activitystates such as sleep may be indicated by particular chemical indicators,e.g. concentration of melatonin in body fluid or other measures (see,for example, U.S. Patent Publication 2005/0215947, which is incorporatedherein by reference in its entirety).

In other embodiments, receiving an input indicative of an activity stateof the subject may include receiving an input representative of physicalactivity of the subject, as indicated at 332 in FIG. 6. The method mayinclude receiving an input representative of motion of the subject (asindicated at 334), receiving an input representative of the bodyposition or posture of the subject (as indicated at 336), receiving aninput from a pressure sensor (as indicated at 338), receiving an inputfrom a force sensor (as indicated at 340), receiving an input from anaccelerometer (as indicated at 342), receiving an input from a gyro (asindicated at 344), receiving an input from a switch (as indicated at346), such as, for example a mercury switch, or receiving an input froma piezoelectric device (as indicated at 348). Other activity sensingdevices, as known to those of skill in the art, may be used as well.

A rest or waking state may be determined based on physical activity. Forexample, resting state may be associated with a lying down postureand/or low level of motion or activity, while a waking or active statemay be associated with an upright posture and/or a higher level ofactivity. A physical activity sensor may be configured to generate asignal indicative of motion or acceleration of the at least a portion ofthe body of the subject innervated by the peripheral neural structure.In some embodiments, the physical activity sensor may be configured togenerate a signal indicative of a body position or posture of thesubject. Physical activity sensors may sense various aspects of postureor movement (amplitude, frequency, direction, etc.) and may includevarious types of sensors, singly or in combination. For example, seeU.S. Pat. No. 5,031,618, which is incorporated herein by reference inits entirety.

Examples of physiological and physical sensors are provided in TheBiomedical Engineering Handbook, Second Edition, Volume I, J. D.Bronzino, Ed., Copyright 2000, CRC Press LLC, section V, pp. V-1-51-9,which is incorporated herein by reference.

FIG. 7 illustrates further variants of the method shown generally inFIG. 4. The method of FIG. 7 includes the steps of producing areversible conduction block in a peripheral neural structure of asubject with a magnetic field while the subject is in a first activitystate (step 400), reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate (step 402), receiving an input indicative of an activity state ofthe subject, wherein the input is indicative of at least one of a firstactivity state and a second activity state of the subject (404) andrepeating the steps of producing a reversible conduction block in aperipheral neural structure of a subject with a magnetic field while thesubject is in a first activity state and reversing the reversibleconduction block in the peripheral neural structure of the subject topermit conduction in the peripheral neural structure when the subject isin a second activity state (step 406). The method further includesreceiving an input indicative of a user instruction, as indicated at408.

Receiving an input indicative of a user instruction may includereceiving a signal from a user input device, as indicated at 410, whichmay include, for example, receiving a signal from a voice or soundactivated input, as indicated at 412, a switch or knob, as indicated at414, a keyboard, as indicated at 416, a mouse, as indicated at 418, atouchscreen, as indicated at 420, or any sort of input device allowing auser to enter an instruction or select an option from a list of possibleoptions, as known to those of skill in the art. User instructions mayalso be received from user-controlled intermediate device; e.g., a userinstruction may be transmitted from a remote controller, a cell phone orremote computer operated by the user. The user may be a medical careprovider, for example. Instructions may be transmitted electronically,electromagnetically, optically, acoustically, mechanically, or by othermethods known to those of skill in the art, via one or more device ortransmission media.

Receiving an input indicative of a user instruction may includereceiving an input indicative of an instruction to modify a definitionof a first activity state or receiving an input indicative of aninstruction to modify a definition of a second activity state. Forexample, the definition of a first or second activity state may includea threshold level, e.g. as depicted in FIG. 5, at reference number 260.

As depicted in FIG. 7, receiving an input indicative of an activitystate of the subject may in some embodiments include receiving an inputindicative of a user instruction as an alternative to sensing aparameter indicative of the activity state of the subject (e.g., aphysical or physiological activity). In other embodiments (notdepicted), receiving an input indicative of a user instruction, may beperformed in addition to sensing a parameter indicative of the activitystate of the subject. For example, a user input may be used to overridedelivery of blocking stimuli determined from a sensed parameter, or tomodify a pattern of delivery of blocking stimuli.

A method as shown generally in FIGS. 4, 6 and 7 may include producing areversible conduction block in a peripheral neural structure of asubject with a blocking stimulus source positioned in proximity to thebody of the subject. In some embodiments, a blocking stimulus sourceworn on the body of the subject. For example, the blocking stimulussource may be located in or on a wrap adapted to be positioned around atleast a portion of the body of the subject, in or on a bracelet, anklet,or cuff configured to be worn on a limb of the subject, or in or on acollar or necklace configured to be worn on a neck of the subject.

FIG. 8 depicts an embodiment of a neural modulation system 450 thatincludes a signal input structure 452 configured to receive a signal 454indicative of an activity state of at least a portion 456 (in this case,the forearm) of a body of a subject 458 innervated by a peripheralneural structure 460, a signal processing portion 462 configured todistinguish a first activity state of the at least a portion 456 of thebody of the subject 458 innervated by the peripheral neural structure460 from a second activity state of the at least a portion 456 of thebody of the subject 458 innervated by the peripheral neural structure460 from the signal 454 received at the signal input structure 452 andgenerate a blocking stimulus control signal 464 for driving productionof a magnetic field blocking stimulus configured to reversibly blockconduction in the peripheral neural structure 460 of the subject duringat least a portion of the first activity state, and a blocking stimulussource 466 configured to be worn on the body of the subject 458 and toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal 464. Signal 454 may be produced by sensor 468 inresponse to activity of portion 456 of body of subject 458. Sensor 468may be, for example, an electrode for sensing electromyographic (EMG)activity reflective of muscle activity.

The blocking stimulus source may be located in or on a wrap adapted tobe positioned around at least a portion of the body of the subject, inor on a bracelet, anklet, or cuff configured to be worn on a limb of thesubject or collar or necklace configured to be worn on a neck of thesubject. In some embodiments, the signal processing portion may also beconfigured to be worn on the body of the subject. The signal processingportion may be packaged with the blocking stimulus source in a packageconfigured to be worn on the body of the subject, e.g. as shown in FIG.8. In other embodiments, the signal processing portion may be configuredto be located at a location remote from the body of the subject. FIG. 8illustrates an embodiment of a system in which a blocking stimulussource 466 is located in an arm band (or bracelet/cuff) 470 configuredto be worn on a forearm 456 of a subject. Blocking stimulus source 466includes a pair of magnetic stimulating coils 472 and 474 configured toproduce hyperpolarization of a portion of peripheral neural structure460. The magnetic field is produced by current flowing through coils 472and 474, as indicated by the black arrows.

In this and other embodiments in which the blocking stimulus source isworn on the body of the subject or otherwise positioned in proximity tothe body of the subject, the blocking stimulus source (e.g. blockingstimulus source 1460) may include, for example, surface electrodesplaced on the skin of a subject over a neural structure for blockingand/or stimulating a neural structure, e.g. as described in Bostock etal. (“Threshold tracking techniques in the study of human peripheralnerve”; Muscle & Nerve; February 1998; pp. 137-158), which isincorporated herein by reference in its entirety. Blocking may beproduced with hyperpolarizing stimuli applied for the duration of theblocking period

Blocking may also be produced with high frequency stimuli. See, forexample, Kilgore and Bhadra (“Nerve conduction block utilizinghigh-frequency alternating current”; Medical & Biological Engineering &Computing; 2004; pp. 394-406; Vol. 42), Zhang et al. (“Simulationanalysis of conduction block in Myelinated axons induced byhigh-frequency biphasic rectangular pulses”; IEEE Transactions onBiomedical Engineering; July 2006; pp. 1433-1436; Vol. 53, No. 7), Zhanget al. (“Mechanism of nerve conduction block induced by high-frequencybiphasic electrical currents”; IEEE Transactions on BiomedicalEngineering; December 2006; pp. 2445-2454; Vol. 53, No. 12.), and Tai etal. (“Simulation analysis of conduction block in unmyelinated axonsinduced by high-frequency biphasic rectangular electrical currents”;IEEE Transactions on Biomedical Engineering; July 2005; pp. 1323-1332;Vol. 52, No. 7), all of which are incorporated herein by reference intheir entirety.

FIG. 9 illustrates a number of blocking stimulus patterns. In someembodiments, a blocking stimulus sufficient to produce a reversibleconduction block of at least a portion of a peripheral neural structureof a subject may be applied substantially continuously during theblocking period. Trace 500 represents the activity state of a subject asa function of time, as indicated on axis 562. Trace 510 depicts anexample of a blocking stimulus that is applied substantiallycontinuously during each blocking period, with the blocking periodscorresponding to occurrences of a first activity state, as indicated intrace 500. Such an application pattern may be appropriate forapplication of a stimulus that produces blocking by hyperpolarization ofaxonal membranes.

In other embodiments, a blocking stimulus sufficient to produce areversible conduction block of at least a portion of a peripheral neuralstructure of a subject may be applied intermittently during the blockingperiod. For example, a blocking stimulus sufficient to produce areversible conduction block of at least a portion of a peripheral neuralstructure of a subject may be applied intermittently at a fixedrepetition rate during the blocking period. A high frequency stimulus asdescribed elsewhere herein is an example of a blocking stimulus that isapplied intermittently. Traces 520 and 530 in FIG. 9 are two examples ofblocking stimuli applied intermittently during the blocking period.Blocking stimuli may include different combinations of pulse duration,pulse amplitude, pulse frequency, duty cycle, etc. In trace 530, pulseamplitude varies over time during the blocking period. In trace 540pulse duration and interval vary over time during the blocking period.In some embodiments, the blocking stimulus may be applied according to aprogrammed pattern during at least a portion of the blocking period. Theprogrammed pattern may specify a blocking stimulus amplitude that variesover time during the blocking period, as depicted in trace 550. Inaddition, a programmed pattern may specify application of blockingstimulus pulses intermittently during the blocking period in which theamplitude of the stimulus pulses varies over time during the blockingperiod, as illustrated in trace 530, or in which one or both of theduration of the stimulus pulses or interval between the stimulus pulsesvaries over time during the blocking period, as illustrated in trace540.

Various configurations of stimulus may be used; while for simplicityrectangular pulses have been depicted in most of the figures, the pulsemay ramp up gradually when it is applied, and/or may decay graduallywhen removed, as depicted in Trace 560 of FIG. 9, or may have variousother waveforms, as illustrated in trace 550.

A reversible conduction block may be produced utilizing various types ofmagnetic blocking stimuli. For example, producing a reversibleconduction block may include applying a magnetic field to at least aportion of the peripheral neural structure. The magnetic field may be astatic or quasi-static magnetic field. In some embodiments, producing areversible conduction block may include applying a pulsed magnetic fieldto at least a portion of the peripheral neural structure. In still otherembodiments, producing a reversible conduction block may includeapplying an oscillating magnetic field, or other cyclical, periodic, ortime-varying magnetic field or to at least a portion of the peripheralneural structure.

Methods as described herein may include storing or saving informationregarding device operation on the device, or transmitting suchinformation to a remote location for storage or evaluation. Informationmay include, but is not limited to including device settings, parametersand other information relating to production of blocking and reversingstimuli, and sensed activity level or activity state of a subject,regarding producing a reversible conduction block.

In some embodiments, methods as described herein may include producing areversible conduction block in a peripheral neural structure of asubject with a blocking stimulus source configured to be positionedbeneath at least a portion of the body of the subject. For example, invarious embodiments, the blocking stimulus source may be located in oron a chair, bed, pad, cushion, or any other structure on which at leasta portion of the body of the subject may rest. If only a portion of thesubject's body is to be subjected to the blocking stimulus, a structurehaving a size and structure suited to the portion of the body may beused. For example, if the body portion is the lower leg, the blockingstimulus source may be included in a footstool, for example. If the bodyportion is the arm, the blocking stimulus source may be included in atable top, arm rest, or sling. If the blocking stimulus source isincluded in a pad or cushion of an appropriate size, the pad or cushionmay be placed on any surface (a chair, stool, table top, the subject'slap, a bed, the ground, etc.) and the body portion may then bepositioned above the pad or cushion.

FIG. 10 depicts an embodiment of a neural modulation system 600 in whicha blocking stimulus source 602 is located in chair 604 on which thesubject 606 may be seated. In the embodiment of FIG. 10, neuralmodulation system 600 includes a signal input structure 608 configuredto receive a signal 610 indicative of an activity state of at least aportion 612 of a body of a subject 606 innervated by a peripheral neuralstructure 614, a signal processing portion 616 configured to distinguisha first activity state of the at least a portion 612 of the body of thesubject 606 innervated by the peripheral neural structure 614 from asecond activity state of the at least a portion 612 of the body of thesubject 606 innervated by the peripheral neural structure 614 from thesignal 610 received at the signal input structure 608 and generate ablocking stimulus control signal 618 for driving production of amagnetic field blocking stimulus 620 configured to reversibly blockconduction in the peripheral neural structure 614 of the subject duringat least a portion of the first activity state, and blocking stimulussource 602 configured to be positioned beneath at least a portion 612 ofthe body of the subject 606 and to produce a magnetic field blockingstimulus 620 responsive to the blocking stimulus control signal 618.Blocking stimulus source 602 may be configured to be located in or on achair 604, as depicted in FIG. 10. Signal 610, which is indicative of anactivity state of a least portion 612 of the body of the subject 606 maybe produced by a sensor 622, which in the present example is a pressurethat is activated when subject 606 sits in chair 604. It is presumedthat portion 612 (the limb of the subject) is substantially immobile andinactive when subject 606 is sitting.

FIG. 11 depicts an embodiment of a system in which a blocking stimulussource is located in a bed 650 upon which the subject 652 lies. In theembodiment of FIG. 11, a subject 652 rests on a bed 650. Blockingstimulus source 654 is positioned below a portion 656 of the body ofsubject 652. User input device 658 (in this example, a switch deviceincluding a push-button 660 that may be depressed by subject 652 toindicate the beginning and end of a rest period) provides a signal 662to signal processing portion 664 on cable 666, representing the activitystate of the subject. As described in connection with other embodiments,signal processing portion 664 controls production of a blocking stimulus668 by blocking stimulus source 654.

A method as illustrated generally in, e.g. FIG. 4 may in someembodiments include producing a reversible conduction block in aperipheral neural structure of a subject with a blocking stimulus sourceimplanted within the body of the subject. FIG. 12 depicts an embodimentof a system in which a blocking stimulus source is implanted within thebody of the subject. Neural modulation system 700 as depicted in FIG. 12includes signal input structure 702 configured to receive a signal 704indicative of an activity state of at least a portion 706 of a body of asubject 708 innervated by a peripheral neural structure 710, a signalprocessing portion 712 configured to distinguish a first activity stateof the at least a portion 706 of the body of the subject 708 innervatedby the peripheral neural structure 710 from a second activity state ofthe at least a portion 706 of the body of the subject 708 innervated bythe peripheral neural structure 710 from signal 704 received at thesignal input structure 702 and generate a blocking stimulus controlsignal 714 for driving production of a magnetic field blocking stimulus716 configured to reversibly block conduction in the peripheral neuralstructure 710 of subject 708 during at least a portion of the firstactivity state, and a blocking stimulus source 718 configured to beimplanted within the body of the subject 708 and to produce a magneticfield blocking stimulus 716 responsive to the blocking stimulus controlsignal 714. As can be seen in greater detail in the inset, in thisexample, blocking stimulus source 718 includes a bipolar arrangement ofmagnetic coils, including two coils 720 and 722 arranged so that currentflows through the two coils in opposite directions, as indicated by theblack arrows. Several types of stimulus coil configurations aredescribed, for example, in Hsu, K.-H. and Durand, D. M.; “Prediction ofNeural Excitation During Magnetic Stimulation Using Passive CableModels”; 2000; IEEE Trans. Biomed. Engr; Vol. 47, No. 4; pp. 463-471;Hsu, K.-H.; Nagarajan, S. S.; and Durand, D. M.; “Analysis of Efficiencyof Magnetic Stimulation”; 2003; IEEE Trans. Biomed. Engr. Vol. 50, No.11; pp. 1276-2385; and Hsu, K.-H. and Durand, D. M.; “A 3-D DifferentialCoil Design for Localized Magnetic Stimulation”; 2001; IEEE Trans.Biomed. Engr; Vol. 48, No. 10; pp. 1162-1168; all of which areincorporated by reference in their entirety. Magnetic field blockingstimuli may be delivered with these and other types and configurationsof coils designed to be positioned near, adjacent to, within or around aperipheral neural structure. For example, see U.S. Pat. No. 3,841,306,which is incorporated herein by reference. Implanted coils may beconnected to a power source within or external to the body of thesubject, via a wired or wireless connection (see, e.g. US 2006/0190053,which is incorporated herein by reference in its entirety.) In theexample of FIG. 12, blocking stimulus source 716 is implanted, but theneural modulation system 700 includes an external portion 726, which maybe worn on the wrist in a manner similar to a wristwatch. In theembodiment of FIG. 12, external portion 726 includes signal processingportion 712 and sensor 728, a motion sensor which detects movement ofportion 706 of the body of subject 708, and generates signal 704, whichis provided to signal input structure 702, as discussed above.

FIG. 13 depicts a related method, which includes the steps of producinga reversible conduction block in a peripheral neural structure of asubject with a magnetic field while the subject is in a first activitystate at 750; reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate at 752; wherein the method further includes reversing thereversible conduction block in the peripheral neural structure of thesubject to permit conduction in the peripheral neural structure when thesubject is in a second activity state by removing a blocking stimulusused to produce the reversible conduction block in the peripheral neuralstructure of the subject, as indicated at 754; and repeating the stepsof producing a reversible conduction block in a peripheral neuralstructure of a subject with a magnetic field while the subject is in afirst activity state and reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate, as indicated at 756.

In some embodiments, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure, a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure, generate a blocking stimuluscontrol signal for driving production of a magnetic field blockingstimulus configured to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state and generate a release stimulus control signal forcontrolling discontinuation of production of the magnetic field blockingstimulus when the subject is in the second activity state, a sensoroperatively connected to the signal input structure and configured togenerate the signal indicative of an activity state of at least aportion of a body of a subject innervated by a peripheral neuralstructure responsive to an activity of the at least a portion of thebody of the subject, and a blocking stimulus source configured toproduce a magnetic field blocking stimulus responsive to the blockingstimulus control signal. A release stimulus control signal may bedelivered to the blocking stimulus source from the signal processingportion on the same line or channel as the blocking stimulus controlsignal, or it may be provided on a separate line or channel.

The signal processing portion may be configured to repetitively generatethe blocking stimulus control signal for driving production of amagnetic field blocking stimulus configured to reversibly blockconduction in the peripheral neural structure of the subject during atleast a portion of the first activity state and the release stimuluscontrol signal for controlling discontinuation of production of theblocking stimulus when the subject is in the second activity state.

In some embodiments, the signal processing portion may be configured torepetitively generate the blocking stimulus control signal for drivingproduction of a magnetic field blocking stimulus configured toreversibly block conduction in the peripheral neural structure of thesubject during at least a portion of the first activity state and therelease stimulus control signal for controlling discontinuation ofproduction of the magnetic field blocking stimulus when the subject isin the second activity state over a period of time sufficient to producemodulation of an immune response in a region innervated by theperipheral neural structure. Modulation of immune response may beassessed according to methods as discussed elsewhere herein.

In some embodiments, the signal processing portion may be configured togenerate the blocking stimulus control signal for driving production ofa magnetic field blocking stimulus configured to reversibly blockconduction in the peripheral neural structure of the subject during atleast a portion of the first activity state and the release stimuluscontrol signal for controlling discontinuation of production of themagnetic field blocking stimulus when the subject is in the secondactivity state cyclically, wherein each cycle includes a blocking periodduring which a magnetic field blocking stimulus sufficient to producereversible conduction block in a peripheral neural structure of asubject is produced while the subject is in a first activity state and arelease period during which no magnetic field blocking stimulus isdelivered, e.g., as illustrated in FIG. 5.

The signal processing portion may be configured to generate the blockingstimulus control signal for driving production of a magnetic fieldblocking stimulus configured to reversibly block conduction in theperipheral neural structure of the subject during at least a portion ofthe first activity state and the release stimulus control signal forcontrolling discontinuation of production of the magnetic field blockingstimulus when the subject is in the second activity state cyclically ata rate of one cycle per day.

The signal processing portion may be configured to generate the magneticfield blocking stimulus control signal for driving production of amagnetic field blocking stimulus configured to reversibly blockconduction in the peripheral neural structure of the subject during atleast a portion of the first activity state and generate the releasestimulus control signal for controlling discontinuation of production ofthe magnetic field blocking stimulus when the subject is in the secondactivity state in alternation according to a pre-set schedule.

Repetitive or cyclical generation of blocking stimuli may be performedas described herein, under the control of software, hardware, or otherelectrical circuitry by methods known to those of skill in the art.

As shown in FIG. 14, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a magnetic field while the subject is in a firstactivity state (step 800), reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate by applying a reversing stimulus configured to counter theblocking stimulus used to produce the reversible conduction block in theperipheral neural structure of the subject (step 802), and repeating thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject while the subject is in a first activity stateand reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 804).

A reversing stimulus may be any stimulus sufficient to counter theblocking stimulus and return the nerve to a normally conductive state. Areversing stimulus may be of the same type or modality as the blockingstimulus (e.g., if the blocking stimulus is a magnetic field, thereversing stimulus may be a magnetic field of the opposite polarity) orreversing stimulus may be of a different type or modality than theblocking stimulus (e.g., the blocking stimulus may be a magnetic field,and the reversing stimulus may be an electrical field, a chemicalstimulus, or a thermal stimulus). The reversing stimulus may cancel oroppose the effect of the blocking stimulus, and may be delivered witheither the same stimulus source as the blocking stimulus, or anotherstimulus source.

FIG. 15 illustrates an embodiment of a neural modulation system 850 thatincludes separate blocking stimulus source and reversing stimulussources. Neural modulation system 850 includes a signal input structure852 configured to receive a signal 854 indicative of an activity stateof at least a portion 856 of a body of a subject innervated by aperipheral neural structure 860, and a signal processing portion 862configured to distinguish a first activity state of the at least aportion 856 of the body of the subject innervated by the peripheralneural structure 860 from a second activity state of the at least aportion 856 of the body of the subject innervated by the peripheralneural structure 860 from signal 854 received at signal input structure852, generate blocking stimulus control signal 864 for drivingproduction of a magnetic field blocking stimulus 866 configured toreversibly block conduction in the peripheral neural structure 860 ofthe subject during at least a portion of the first activity state, andgenerate a reversing stimulus control signal 868 for driving productionof a reversing stimulus 870 to counter magnetic field blocking stimulus866 used to produce the reversible conduction block in the peripheralneural structure 860 of the subject, a blocking stimulus source 872configured to produce a magnetic field blocking stimulus 866 responsiveto the blocking stimulus control signal 864, and a reversing stimulussource 874 configured to produce a reversing stimulus 870 responsive tothe reversing stimulus control signal 868.

The reversing stimulus may be any type of stimulus that serves toreverse the effect of the blocking stimulus to bring the neuralstructure back to (or toward) its previous conductivity state. In someembodiments, the reversing stimulus source may be of the same type asthe blocking stimulus source; for example, the reversing stimulus sourcemay include an electric field source or a magnetic field source. In someembodiments, the reversing stimulus source may include at least aportion of the blocking stimulus source, while in other embodiments, thereversing stimulus source may be a different stimulus source of the sametype as the blocking stimulus source. In some embodiments, the reversingstimulus source may include a different type of stimulus source than theblocking stimulus source. For example, in a neural modulation systemthat includes a magnetic blocking stimulus source, the reversingstimulus source may include one or more of a heating element, a coolingelement, an electromagnetic transducer, an optical photon source, anacoustic energy source, or a chemical agent source.

Applying a reversing stimulus to counter the blocking stimulus used toproduce the reversible conduction block in the peripheral neuralstructure of the subject may include applying an electric field to atleast a portion of the peripheral neural structure. The electric fieldused as a reversing stimulus may be a pulsed electric field applied toat least a portion of the peripheral neural structure, or it may becyclical or time-varying electric field.

In some embodiments, applying a reversing stimulus to counter theblocking stimulus used to produce the reversible conduction block in theperipheral neural structure of the subject may include applying amagnetic field to at least a portion of the peripheral neural structure.The magnetic field used as a reversing stimulus may be a pulsed magneticfield to at least a portion of the peripheral neural structure.

In some embodiments, applying a reversing stimulus to counter theblocking stimulus used to produce the reversible conduction block in theperipheral neural structure of the subject may include applyingelectromagnetic energy to at least a portion of the peripheral neuralstructure. Applying a reversing stimulus to counter the blockingstimulus used to produce the reversible conduction blocking in theperipheral neural structure of the subject may include heating orcooling at least a portion of the peripheral neural structure. FIG. 16shows a further extension of the method of modulating neural activityoutlined in FIG. 4. The method includes producing a reversibleconduction block in a peripheral neural structure of a subject with amagnetic field while the subject is in a first activity state (step900), reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 902),repeating the steps of producing a reversible conduction block in aperipheral neural structure of a subject with a magnetic field while thesubject is in a first activity state and reversing the reversibleconduction block in the peripheral neural structure of the subject topermit conduction in the peripheral neural structure when the subject isin a second activity state (step 904), determining that producing thereversible conduction block in the peripheral neural structure of thesubject with a magnetic field while the subject is in a first activitystate results in a desired effect in the subject (step 906), andproducing a non-reversible conduction block in the peripheral neuralstructure of the subject (step 908). A desired effect may be, forexample, reduction or elimination of pain, undesired sensations,inflammation, immunological or physiological problems caused orcontributed to by peripheral neural activity in the blocked peripheralneural structure. Determination that a desired effect has been producedmay be made through sensing of various physiological or physicalparameters, or by qualitative or subjective reporting obtained from thesubject.

A non-reversible conduction block may be produced in various ways. Asshown in further detail in FIG. 17, the method may in FIG. 16 mayinclude producing a non-reversible conduction block by applying heat toat least a portion of the peripheral neural structure of the subject,for example with a Peltier device. Various other techniques can be usedto apply heat, without limitation, as are known to those of skill in theart. Some examples include: electrical current, optical photons,ultrasound, the use of a resistive heater, etc. See, for example, U.S.Published Patent Application 2005/0288730, which is incorporated hereinby reference. Heat may cause non-reversible conduction block by variousmechanisms, e.g. thermal ablation of tissue or stimulation of apoptosis.See, for example, the method as disclosed in U.S. Pat. No. 6,405,732,which is incorporated herein by reference in its entirety. The presentmethod is not limited to any particular mechanism of producing anon-reversible conduction block through application of heat. Anon-reversible conduction block may be produced by cooling or removingheat from at least a portion of the peripheral neural structure of thesubject, for example with a Peltier device or with a fluid heat transferdevice, applying an electrical current to at least a portion of theperipheral neural structure of the subject, delivering acoustic energyto at least a portion of the peripheral neural structure of the subject,delivering photons to at least a portion of the peripheral neuralstructure of the subject, delivering a chemical agent (e.g. capsaicin)to least a portion of the peripheral neural structure of the subject, orby surgical transection of at least a portion of the peripheral neuralstructure of the subject.

Producing a reversible conduction block may include producingsubstantially complete blockage of conduction in the peripheral neuralstructure of the subject. Alternatively, in some cases only partialblockage of conduction may be obtained, e.g. as depicted in FIGS. 2E and2F. Completeness of blockage may be assessed by measuring neuralactivity by known methods by delivering a well-defined stimulus on oneside of the blocked region and measuring the evoked neural activity onthe other side of the blocked region and, optionally, comparing theevoked activity to activity measured at the same site prior to blockingof conduction or at an location upstream of the block, either before orafter blocking.

FIG. 18 depicts a further embodiment of a neural modulation system thatis similar to previously described systems, but in addition includes anon-reversible blocking source. Neural modulation system 925 may be asignal input structure 927 configured to receive signal 929 indicativeof an activity state of at least a portion 931 of a body of a subjectinnervated by a peripheral neural structure 935, and a signal processingportion 937 configured to distinguish a first activity state of the atleast a portion 931 of the body of the subject innervated by theperipheral neural structure 935 from a second activity state of the atleast a portion 931 of the body of the subject innervated by theperipheral neural structure 935 from signal 929 received at signal inputstructure 927 and generate a blocking stimulus control signal 939 fordriving production of a magnetic field blocking stimulus 941 configuredto reversibly block conduction in the peripheral neural structure 935 ofthe subject during at least a portion of the first activity state,determine that producing the reversible conduction block in peripheralneural structure 935 of the subject while the subject is in a firstactivity state results in a desired effect in the subject, and generatea non-reversible blocking source control signal 943 for driving anon-reversible blocking source 945 to perform an action adapted forproducing a non-reversible conduction block in peripheral neuralstructure 935 of the subject, a blocking stimulus source 947 configuredto produce a magnetic field blocking stimulus 941 responsive to theblocking stimulus control signal 939, and a non-reversible blockingsource 945 configured to perform an action adapted for producing anon-reversible conduction block in the peripheral neural structure ofthe subject responsive to the non-reversible blocking source controlsignal.

FIG. 18 depicts a system 925 in which blocking stimulus source 947includes a pair of magnetic coils 951 and 953, and non-reversibleblocking source 945 is an ultrasonic transducer. In other embodiments,the non-reversible blocking source may include an electrical currentsource, a heat source, an acoustic energy source (of which an ultrasonictransducer is an example), a photon source, or a chemical agent source.A heat source may include, but is not limited to, an appropriatelyconfigured Peltier device, a light source, or a resistive element. Insome embodiments, the non-reversible blocking source may include acooling source, such as an appropriately configured Peltier device or areservoir containing a chemical composition or mixture capable ofundergoing a controllable endothermic reaction. In general, anon-reversible blocking source may be any source of any type of energy,material, or action sufficient to damage or destroy the peripheralneural structure to produce permanent (or substantially permanent)blockage of nerve conduction. As a further example, in some embodiments,the non-reversible blocking source may include a surgical transectionmechanism. Coils 951 and 953 and non-reversible blocking source 945 arepowered by and connected to signal processing portion 937 via leads 957,959, and 961, respectively. Sensor 963, which senses activity of portion931 of the body the subject, provides an input to signal input structure927.

FIG. 19 illustrates a further variant of a method of modulating neuralactivity, which may include producing a reversible conduction block of asubset of nerve fibers in a peripheral neural structure of a subjectwith a magnetic field while the subject is in a first activity state(step 950), reversing the reversible conduction block of the subset ofnerve fibers in the peripheral neural structure of the subject to permitconduction in the subset of nerve fibers in the peripheral neuralstructure when the subject is in a second activity state (step 952), andrepeating the steps of producing a reversible conduction block in thesubset of nerve fibers in a peripheral neural structure of a subjectwith a magnetic field while the subject is in a first activity state andreversing the reversible conduction block in the subset of nerve fibersin the peripheral neural structure of the subject to permit conductionin the subset of nerve fibers in the peripheral neural structure whenthe subject is in a second activity state (step 954). In differentvariations of the method (indicated with dashed boxes in FIG. 19) thesubset of nerve fibers in the peripheral neural structure of the subjectmay include nerve fibers within a selected diameter range, as indicatedat 956, within a selected spatial distribution within the peripheralneural structure, as indicated at 958, within selected fascicles and/orwithin the peripheral neural structure, as indicated at 960. Variousmethods of exciting or blocking nerve fibers selectively with respect tofiber diameter, location within a nerve or nerve bundle, or within afascicle are described, for example, in Tarler and Mortimer (“Selectiveand independent activation of four motor fascicles using a four contactnerve-cuff electrode”; 2004; IEEE Trans. Neural Syst. Rehab. Eng.”; Vol.12; pp. 251-257), Vessela et al. (“Peripheral nerve magneticstimulation: influence of tissue non-homogeneity” BioMedical EngineeringOnLine; 23 Dec. 2003; located at:http://www.biomedical-engineering-online.com/content/2/1/19), Olree andHorch (“Differential activation and block of peripheral nerve fibers bymagnetic fields”; Muscle & Nerve; 2006; pp. 189-196; Vol. 34, WileyPeriodicals), and U.S. Pat. No. 5,540,730, all of which are fullyincorporated herein by reference.

Alternatively, or in addition, the subset of nerve fibers in theperipheral neural structure of the subject may include nerve fibersincluding a selected molecular feature, as indicated at 962. Selectiveblocking of nerve fibers having particular molecular features has beendescribed in Binshtok, A. M.; Bean, B. P. and Woolf, C. J.; “Inhibitionof nociceptors by TRPV1-mediated entry of impermeant sodium channelblockers”; Nature, Vol. 449, 2007; pp. 607-611; doi:10.1038/nature06191and McCleskey, E. M. “A local route to pain relief”; Nature; Vol. 449;2007; pp. 545-546, which are incorporated herein by reference.Responsiveness of nerve fibers having selected molecular features tomagnetic blocking stimuli may be modulated, for example, by materialstargeted to nerve fibers having the molecular feature. A variety ofmolecular markers for specific types of nerve fibers are known. Forexample, neurofilament (NF) is a highly specific marker for Myelinatednerve fibers; substance P and calcitonin gene-related protein (CGRP) aremarkers for sensory nerve fibers (both A and c-type); Acetylcholine(Ach) is a marker for cholinergic nerve fibers, which may be sympatheticpre-ganglionic fibers or parasympathetic pre-ganglionic orpost-ganglionic fibers; tyrosine hydroxylase (TH) is specific foradrenergic nerve fibers (sympathetic postganglionic neurons). Forexample, see Tokushige, N.; Markham, R.; Russell, P. and Fraser, I. S.;“Nerve fibres in peritoneal endometriosis”; Human Reproduction; 2006;Vol. 21; No. 11; pp. 3001-3007, which is incorporated herein byreference in its entirety. Cyclin dependent kinase 5 (Cdk5) is expressedin nociceptive fibers (Pareek, T. K.; Keller, J.; Kesavapany, S.; Pant,H. C.; Iadarola, M. J.; Brady, R. O.; and Kulkami, A. B.;“Cyclin-dependent kinase 5 activity regulates pain signaling”; PNAS;Jan. 17, 2006; Vol. 103, No. 3; pp. 791-796), incorporated herein byreference in its entirety. Similarly, capsaicin receptor (vanilloidreceptor type 1 (VR1)) and variants thereof, e.g. vanilloid receptorhomologue (VRL1) are expressed in A and C fiber sensory neurons, asdescribed in Ma, Q.-P.; “Vanilloid receptor homologue, VRLI, isexpressed by both A- and C-fiber sensory neurons”; Neuro Report; Vol.12, No. 17; 4 Dec. 2001; pp. 3693, which is incorporated herein byreference in its entirety.

In some embodiments of a neural modulation system, a blocking stimulussource may be configured to produce substantially complete blockage ofconduction in the peripheral neural structure of the subject responsiveto the blocking stimulus control signal. In other embodiments, ablocking stimulus source may be configured to produce blockage of asubset of nerve fibers in the peripheral neural structure of the subjectresponsive to the blocking stimulus control signal, based, for example,upon approaches as described above. The subset of nerve fibers in theperipheral neural structure of the subject may include nerve fiberswithin a selected diameter range, nerve fibers within a selected spatialdistribution within the peripheral neural structure, or nerve fibersincluding a selected molecular feature.

FIGS. 20A-20D depict examples of magnetic field sources that may be usedas blocking stimulus sources in neural modulation systems as describedand depicted generally herein. A magnetic field source may include acoil or other structure through which current may flow to generate amagnetic field; blocking stimulus sources include associated therewithcurrent sources capable of producing current that, when passed throughthe coil, generate a magnetic field of suitable magnitude. Interactionof coil and current to produce a magnetic field are described, forexample, in Hsu, K.-H. Nagarajan, S. and Durand, D. M., “Analysis ofEfficiency of Magnetic Stimulation,” IEEE Trans. Biomed. Engr., Vol. 50,No. 11, November 2003, pp. 1276-1284, which is incorporated herein byreference in its entirety, and other materials incorporated herein byreference. As used herein, the term “coil” refers to various structures;in some embodiments, a coil may include multiple current-carrying loopsand in other embodiments a coil may include a single full or partialloop. While coils may often include generally rounded or circular loops(full or partial) coils are not limited to any particular loopconfiguration.

FIG. 20A depicts a single coil 1000, which may be positioned on or nearskin surface 1002 above peripheral neural structure 1004. The directionof current flow in the coil is indicated by the black arrow.

FIG. 20B illustrates a “butterfly coil” 1018 including a pair of coils1012 and 1014. In the example of FIG. 20B, butterfly coil 1018 isimplanted beneath skin surface 1010, adjacent peripheral neuralstructure 1016.

FIG. 20C illustrates a “3-dimensional differential coil” 1020 of thetype described in Hsu, K.-H. and Durand, D. M., “A 3-D Differential CoilDesign for Localized Magnetic Stimulation,” IEEE Trans. Biomed. Engr.,Vol 48, No. 10, October 2001, pp. 1162-1168, which is incorporatedherein by reference in its entirety. 3-dimensional differential coil”1020 is made up of multiple coils, including coils 1022, 1024 and 1026lying in a first plane, shown here perpendicular to skin surface 1032,and coils 1028 and 1030 lying a second plane, shown here parallel toskin surface 1032. The direction of current flow through the coils isindicated by the black arrows. In FIGS. 20A, 20B, and 20C, it is to beunderstood that magnetic fields for producing blocking of conduction areproduced by current flowing through the coils, supplied by one or morecurrent sources (not shown), as is known to those of skill in the art.Rattay, F. “Modeling the Excitation of Fibers Under Surface Electrodes,”IEEE Trans. Biomed. Engr., Vol. 35, No. 3, March 1988, pp. 199-202,which is incorporated herein by reference, relates potentialdistribution in tissue and “activating function” with the development ofnerve conduction block; and Hsu, K.-H. Nagarajan, S. and Durand, D. M.,“Analysis of Efficiency of Magnetic Stimulation,” IEEE Trans. Biomed.Engr., Vol. 50, No. 11, November 2003, pp. 1276-1284, incorporated byreference herein above, relates magnetic stimulation to potentialdistribution and “activating function”. Hsu, K. H and Durand, D. M.,“Prediction of Neural Excitation During Magnetic Stimulation UsingPassive Cable Models,” IEEE Trans. Biomed. Engr., Vol 47, No. 4, April2000, pp. 463-471, which is incorporated herein by reference in itsentirety, provides further guidance regarding activation of neuralstructures with magnetic stimuli.

As shown in FIG. 20D, in another alternative embodiment, a blockingstimulus source 1040 may include one or more fixed magnets, 1041 and1042, which may be adjustably positioned relative to skin surface 1043and peripheral neural structure 1045 by positioning mechanisms 1047 and1049, respectively. The positions of fixed magnets 1041 and 1042 may beadjusted responsive to a blocking stimulus control signal.

Methods of neural modulation as described herein may be implemented witha neural modulation system 1050 as illustrated generally in FIG. 21,which depicts a variation of the system shown in FIG. 3. Basiccomponents of neural modulation system 1050 include a signal inputstructure 1052, sensor 1054, and signal processing portion 1056. Signalinput structure 1052 may be operatively connected to sensor 1054 andconfigured to receive a signal indicative of an activity state of atleast a portion of a body of a subject 1055 innervated by a peripheralneural structure. Signal input structure 1052, and other signal inputstructures described elsewhere herein, may be of various typesconfigured to accept or receive signals of various types. Such signalinput structures are known to those of skill in the art, and mayinclude, but are not limited to, analog or digital inputs capable ofaccepting or receiving electrical, optical, acoustic, electromagnetic,or other types of signals. Signals may be accepted or received at asignal input structure through direct physical contact (e.g., anelectrical contact), or by reception of a signal transmitted through oracross a medium (e.g., via an inductive, optical, or electromagneticlink). Sensor 1054 may be operatively connected to the signal inputstructure 1052 and configured to generate a signal indicative of anactivity state of a portion of the body of the subject 1055 innervatedby the peripheral neural structure responsive to an activity of theportion of the body 1055. Signal processing portion 1056 may beconfigured to distinguish a first activity state at least partiallybased on the signal received by the signal input structure 1052, and togenerate a blocking stimulus control signal 1058 for driving productionof a blocking stimulus 1060 by blocking stimulus source 1064.

FIG. 21 depicts in schematic form an embodiment of a system 1050, inwhich signal processing portion 1056 and signal input structure 1052 arepackaged together in package 1066 and sensor 1054, and blocking stimulussource 1064 is packaged separately. In some embodiments, blockingstimulus source 1064 or portion thereof may be located outside the bodyof the subject, and the blocking stimulus may pass through the skin andunderlying tissue to reach the neural structure that is to be blocked.In other embodiments, a blocking stimulus source may be positionedwithin the body of the subject, either permanently or temporarily.Suitable positioning of the blocking stimulus source will depend uponthe type of blocking stimulus source being used and the type andlocation of the neural structure to be blocked.

Neural modulation system 1050 may optionally include override signalinput structure 1070, as indicated by the dashed box in FIG. 21.Override signal input structure 1070 may be configured to receive asignal indicative of a condition of the body of the subject, and signalprocessing portion 1056 may be configured to override generation of theblocking stimulus control signal 1058 responsive to a signal indicativeof an override condition of the body of the subject on override signalinput structure 1070. Alternatively, override signal input structure1070 may be configured to receive a signal indicative of a conditionexternal to the body of the subject, and signal processing portion 1056may be configured to override generation of the blocking stimuluscontrol signal responsive to a signal indicative of an overridecondition external to the body of the subject on the override signalinput. As a further alternative, or in addition, override signal inputstructure 1070 may be configured to receive a signal from a user inputdevice, and the signal processing portion may be configured to overridegeneration of the blocking stimulus control signal responsive to asignal indicative of a user override request on the override signalinput. The override signal may indicate that it is no longer desirableto apply the blocking stimulus, for reasons of safety, comfort, orconvenience, for example, and may be indicative of a condition of thebody of the subject, or of a condition external to the body of thesubject (e.g., in the environment of the subject). If the overridesignal is detected from a user input device, it may be the same userinput device used in normal operation of the system, and the overridesignal input structure may be the same as the signal input structurethat normally receives input from a user input device.

Sensor 1054 as depicted generally in FIG. 21 (and, in addition, sensorsuse in other embodiments depicted and/or described herein) may includeany of a variety of different types of sensors, including, but notlimited to, pressure sensors, force sensors, chemical sensors (includingbut not limited to sensors capable of sensing pH, gas, ions, proteins,or biomolecules), temperature sensors, electrical sensors (for sensingcurrent, potential, charge, resistance, resistivity, capacitance, orother electrical parameters), magnetic sensors, optical sensors, motionsensors, etc. A single sensor or multiple sensors, of the same ormultiple different types, may be used.

The signal processing portion 1056, as depicted in FIG. 21, may beconfigured to determine the onset of the first activity state andgenerate the blocking stimulus control signal for driving production ofa magnetic field blocking stimulus configured to reversibly blockconduction in the peripheral neural structure of the subject at leastintermittently responsive to detecting the onset of a first activitystate in the subject. In some cases, the signal processing portion maybe configured to generate the blocking stimulus control signal fordriving production of a magnetic field blocking stimulus configured toreversibly block conduction in the peripheral neural structure of thesubject substantially immediately upon detecting the onset of the firstactivity state in the subject. In other cases, the signal processingportion may be configured to generate the blocking stimulus controlsignal for driving production of a magnetic field blocking stimulusconfigured to reversibly block conduction in the peripheral neuralstructure of the subject at a delay interval after detecting the onsetof the first activity state in the subject. The signal processingportion may be configured to initiate a release period during which noblocking stimulus control signal is generated after an intervaldetermined relative to the onset of generation of the blocking stimuluscontrol signal.

In some cases, the signal processing portion may be configured todetermine the onset of the second activity state in the subject andinitiate a release period during which no blocking stimulus controlsignal is generated responsive to detecting the second activity state inthe subject. The signal processing portion may be configured to initiatethe release period substantially immediately upon detection of the onsetof the second activity state in the subject, or to initiate the releaseperiod at a delay interval after detection of the onset of the secondactivity state in the subject.

Components of neural modulation systems of the type described herein maybe packaged in various manners. In some cases, all components of asystem may be packaged together. Such a package may be designed for useoutside the body, or designed for use inside the body in an implantablesystem. However, in many cases it may be desirable to package certaincomponents of the system separately. Communication between systemcomponents may be wireless, e.g. as described in U.S. Pat. No.6,208,894, which is incorporated herein by reference in its entirety.The system may include the capability for remote programming,interrogation, or telemetry, for example as described in U.S. Pat. No.7,263,405, which is incorporated herein by reference in its entirety.

FIG. 22 depicts an example of a neural modulation system 1100 in which asensor (motion sensor 1102) and blocking stimulus source are packagedwith signal processing portion 1106 in package 1108. Motion sensor 1102provides an input to signal processing portion 1106 via signal inputstructure 1110. Signal processing portion 1106 generates blockingstimulus control signal 1112 which drives production of blockingstimulus 1114 by blocking stimulus source 1104. Package 1108 may beadapted to be positioned external to the body of subject 1055, andblocking stimulus 1114 may pass through body tissues to reach peripheralneural structure 1062. Blocking stimulus source 1104 may include coilsconfigured to deliver a magnetic field to the body of the subjectsufficient to produce blocking of a nerve. Package 1108 may beconfigured to secured to a limb (e.g., with a strap or elastic band)over a peripheral neural structure 1062, so that the magnetic blockingstimulus may be delivered to the peripheral neural structure. Generationof blocking stimulus control signal 1112 by signal processing portion1106 may be responsive to a signal from motion sensor 1102, such that ablocking stimulus may be delivered to the peripheral neural structurewhen the limb is not in motion, for example. The peripheral neuralstructure may be, for example, a sensory nerve, and blockage of neuralactivity therein may, for example, reduce or limit pain or inflammation,e.g. of arthritis, peripheral vascular disease, etc. In relatedembodiments, sensor 1102 may be any of various types of sensors, asdescribed elsewhere herein.

FIG. 23 depicts an example of a neural modulation system 1150 in whichan implanted sensor and implanted blocking stimulus source are used. Inthis example, the implanted sensor may be sensing electrode 1152, andthe blocking stimulus source may be an implantable blocking stimulussource 1154, e.g., as described elsewhere herein. Sensing electrode 1152and blocking stimulus source 1154 may be implanted within the body ofsubject 1055, such that sensing electrode 1152 may sense neural ormuscular activity representative of activity of at least a portion ofthe body of the subject, and blocking stimulus source 1154 may deliverblocking stimulus 1156 to a peripheral neural structure, peripheralnerve 1062. As used herein, “implanted” means located or positioned,either temporarily or permanently, within the body of the subject.Signal processing portion 1158 may be packaged separately, e.g. inpackage 1160. Sensing electrode 1152 may provide an input to signalprocessing portion 1158 via signal input structure 1162. Signalprocessing portion 1158 may generate blocking stimulus control signal1164 for driving production of blocking stimulus 1156 by blockingstimulus source 1154. Package 1160 may be implanted within the body ofsubject 1055, or located external to body of subject 1055. In eithercase, signals may be transmitted between signal processing portion 1158and sensing electrode 1152 and blocking stimulus source 1154 via a wireor cable, optical ink, acoustic link, radiofrequency or otherelectromagnetic link, or other wireless communication link, as is knownto those of skill in the art. As discussed in connection with FIG. 24,blockage of neural activity may reduce or limit pain or inflammation. Inone application, for example, sensing electrode 1152 and blockingstimulus source 1154 may be implanted on a sensory nerve innervating alimb, appendage, or joint (for example, a knee) that has suffered injuryand/or damage, with the goal of limiting the progression of arthritisthat would otherwise be associated with the injury or damage.

FIG. 24 depicts in further detail an example of a system 1200 in whichcomponents are packaged so that some can be used locally (e.g. implantedin the body or positioned on or near the body surface) while others areused remotely, which in this context may be in a separate packagelocated relatively close by (i.e. in, on or near the body), or at adistant location such as across a room, in a separate room, or in aseparate building). System 1200 includes local portion 1202 and remoteportion 1204. Local portion 1202 may be implanted in the body of asubject or positioned on or near the body surface, while remote portion1204 may be located remotely from local portion 1202. Local portion 1202may include sensor 1206 and blocking stimulus source 1208. Local portion1202 may also include local circuitry portion 1210 andreceiver/transmitter 1212. A corresponding receiver/transmitter 1214 inremote portion 1204 permits the transmission of data and instructionsbetween local portion 1202 and remote portion 1204. In some embodiments,power may also be transmitted between remote portion 1204 and localportion 1202. Alternatively, or in addition, one or both of localportion 1202 and remote portion 1204 may include a power source (e.g., abattery or other power source as known to those of skill in the art).Remote portion 1204 may include remote circuitry 1216, which may includesignal processing portion 1218. The signal processing portion of thesystem may include only signal processing portion 1218 in remote portion1204, or it may include both signal processing portion 1218 in remoteportion 1204 and signal processing circuitry 1220 in local portion 1202.Alternatively, in some embodiments, the signal processing portion mayinclude signal processing circuitry 1220 in local portion 1202 andremote circuitry 1216 may be devoted to other functions.

Components packaged separately may be operatively connected to othercomponents by cables, a wireless link (which may be optical,electromagnetic, acoustic, etc.). Separately packaged components may besuited for use outside or inside the body. In some embodiments, somecomponents may be positioned inside the body while other are positionedoutside the body during use. In some embodiments, the signal processingportion may be configured to perform encryption of signals transmittedto separately packaged and/or remote components or device portion, e.g.a blocking stimulus control signal. Similarly, the signal processingportion may be configured to perform decryption of signals receivedfrom, e.g., a user input device, via a signal input structure oroverride signal input structure. Encryption/decryption may be performedby standard methods as known to those of skill in the art, for example,as used in computers, networks, mobile telephones, wireless microphones,wireless intercom systems, Bluetooth devices, and so forth.Encryption/decryption may be used in order to provide securetransmission of information, for example for protecting privacy ofpersonal information and/or for avoiding interference between multipledevices used in the same area.

In some embodiments, a user input device may be used in place of (or inaddition to) a sensor in order to provide indication of an activity oruse state of all or a portion of the body of the subject. Such a systemis depicted in schematic form in FIG. 25. As shown in FIG. 25, neuralmodulation system 1250 may include a signal input structure 1252configured to receive a signal 1254 indicative of an activity state ofat least a portion of a body of a subject 1256 innervated by aperipheral neural structure 1258; a user input device (switch 1260)operatively connected to the signal input structure 1252 and configuredto generate a signal 1254 responsive to a user input indicative of anactivity state of at least a portion of a subject 1256 innervated by theperipheral neural structure 1258. For example, switch 1260 may be set tothe “on” setting when the subject is entering a first activity state,and set to the “off” setting when the subject is entering a secondactivity state. Neural modulation system 1250 also includes signalprocessing portion 1262 configured to distinguish a first activity stateof the at least a portion of the body of the subject 1256 innervated bythe peripheral neural structure 1258 from a second activity state of theat least a portion of the body of the subject 1256 innervated by theperipheral neural structure 1258 from the signal 1254 received at thesignal input structure 1252 (e.g., by detecting the “on” or “off”setting of switch 1260); and generate a blocking stimulus control signal1264 for driving production of a blocking stimulus 1266 configured toreversibly block conduction in the peripheral neural structure 1258 ofthe body of subject 1256 during at least a portion of the first activitystate. Blocking stimulus 1266 is produced by a blocking stimulus source(in this example, magnetic field source 1270) responsive to blockingstimulus control signal 1264.

A user of the system depicted in FIG. 25 (the subject or another party,such as a medical care-giver or assistant) may use user input device(e.g., switch 1260) to indicate that the subject is currently resting orinactive (e.g., sitting in a chair or lying in bed) or about to begin aperiod of rest or inactivity, (e.g., by changing the setting of switch,as described above). Similarly, a user of the system may also use theuser input device to indicate the end of a period of rest or inactivity.The user input device may include various types of user input devices,as are known to those of skill in the art. For example, the user inputdevice may include one or more of the following: a voice-activated orother sound-activated input device, e.g. a microphone, a user-activatedswitch or knob, a keyboard, a mouse or other pointing device, atouch-screen or other user activated input devices.

The foregoing are examples, and various other devices that allow thesubject or other user to signal a change (or expected change) inactivity state may be used in practice.

As discussed in connection with systems in which sensors are used toprovide indication of an activity or use state of all or a portion ofthe body of the subject, the various components of the system may bepackaged together or separately, located locally or remotely, inside oroutside the body of the subject, as depicted in FIGS. 10-13. Forexample, FIG. 25 shows an example of a system in which switch 1260 ispackaged separately from the signal processing portion 1262 and islocated outside of the body of subject 1256, while magnetic field source1270 is packaged with signal processing portion 1262. Signal processingportion 1262 and magnetic field source 1270 may be in a packageconfigured to be placed against the subject's body as the subject rests,while switch 1260 may be connected to signal processing portion 1262with a cable, for example (or, alternatively, a wireless connectionssuch as an optical or RF connection). The subject may toggle switch 1260to indicate the beginning or end of a rest period during which theblocking stimulus is to be delivered. Magnetic field source 1270 may beconfigured to generate a magnetic field sufficient to block conductionin peripheral neural structure 1258 (see, e.g. Olree and Horch(“Differential activation and block of peripheral nerve fibers bymagnetic fields”; Muscle & Nerve; 2006; pp. 189-196; Vol. 34, WileyPeriodicals), which is incorporated herein by reference in its entirety.Peripheral neural structure 1258 may be blocked with the goal ofproducing a particular beneficial effect, such as to limit theprogression of an inflammatory process (e.g. in diabetes, arthritis,vascular disease).

FIG. 26 depicts a further example of a system 1300 in which user inputdevice 1302 is packaged separately from signal processing portion 1304,providing signal 1306 to signal input structure 1308. Signal processingportion 1304 generates blocking stimulus control signal 1310, which isprovided (e.g., transmitted) to blocking stimulus source 1312, which isimplanted within the body of subject 1256. As discussed previously,blocking stimulus source 1312 generates blocking stimulus 1314 forblocking conduction in peripheral neural structure 1258 in body ofsubject 1256. Other arrangements of system components are possible, andsystems as described generally herein are not limited to the specificarrangements of components depicted in the figures.

A schematic diagram showing components and operation of a signalprocessing portion 1350 of a neural modulation system 1352 is shown inFIG. 27. The functional relationship of signal processing portion 1350to other components of neural modulation system 1352 is also shown. Asnoted previously, signal processing portion 1350 and other systemcomponents may be powered by a single power source, as shown in FIG. 26as power source 1354; or multiple power sources. Signal processingportion 1350 may receive as input signals from one or more sensors 1356and/or one or more user input devices 1358 via signal input structure1359, and optionally, a signal from override signal input structure1380. Signal processing portion 1350 may generate as output blockingstimulus control signal 1360 for driving blocking stimulus source 1362to produce a blocking stimulus.

Signal processing portion 1350 may include electrical circuitry 1364 forperforming signal processing functions including but not limited toamplification, filtering, signal averaging, thresholding,variable-changing, waveform analysis, variable (e.g., time- orspatial-frequency) domain transformation, convolution, cross-spectralanalysis, feature or pattern recognition or extraction, processingperformed relative to data-stored-in-memory, etc., or a combination orconcatenation of any or all of these, as is known to those of skill inthe art of signal processing, whether such operations may be done insoftware, firmware or hardware or combinations of these. Electricalcircuitry 1364 may also be configured to generate blocking stimuluscontrol signal 1360 for driving blocking stimulus source 1362. Detectionof the onset or end of an activity state is not limited threshold-baseddeterminations, but may include various other types of signal processingas known to those of skill in the art; for example analysis of the trendof the signal may be used to predict the onset of an activity state.Accordingly, operations performed in response to detection ordetermination of the onset of a particular activity state may in somecases be based upon the predicted onset of an activity state, and mayoccur before, after, or simultaneously with the predicted onset of anactivity state. Electrical circuitry or other components of a signalprocessing portion may accordingly be configured to generate a blockingstimulus or to initiate a release period prior to, simultaneously with,or subsequently to the predicted the onset of an activity state in thesubject.

The blocking stimulus may be applied with a repetitive or cyclicalapplication pattern according to a detected signal indicative of atleast one activity state in the subject and/or according to a pre-setschedule. Signal processing portion 1350 may include at least one signalbearing medium 1366 that may contain blocking stimulus pattern 1368,which specifies the configuration (e.g. waveform and timing ofapplication) of a blocking stimulus. Signal bearing medium 1366 may alsoinclude blocking stimulus parameters 1370 related to generating blockingstimulus control signal 1360 according to a detected signal from sensor1356 or user input 1358. Stimulus parameters 1370 may include constantsand/or variables to be used in calculations of blocking stimulus controlsignal 1360 as a function of the detected signal. Signal bearing medium1366 may include instructions 1372, which may relate to one or more ofreceiving or acquiring signals on signal input structure 1359,processing the signals, generating blocking stimulus control signal1360, storing data (e.g. signals or parameters representing some or allof sensor or user input, blocking stimulus control signal, etc.) in datastorage location 1374, and instructions related to transmitting and/orreceiving data or instructions via transmitter/receiver circuitry 1376.Electrical circuitry 1364 and signal bearing medium 1366 may optionallyinclude instructions, patterns, and/or parameters for use in generatingrelease stimulus control signal 1380 for producing discontinuation ofgeneration of a blocking stimulus by blocking stimulus source 1362, andinstruction, patterns, and/or parameters for use in generating reversingstimulus control signal 1382 for driving generation of a reversingstimulus by reversing stimulus source 1384.

In a general sense, those skilled in the art will recognize that thevarious aspects described herein that can be implemented, individuallyand/or collectively, by a wide range of hardware, software, firmware, orany combination thereof can be viewed as being composed of various typesof “electrical circuitry.” Consequently, as used herein “electricalcircuitry” includes, but is not limited to, electrical circuitry havingat least one discrete electrical circuit, electrical circuitry having atleast one integrated circuit, electrical circuitry having at least oneapplication specific integrated circuit, electrical circuitry forming ageneral purpose computing device configured by a computer program (e.g.,a general purpose computer configured by a computer program that atleast partially carries out processes and/or devices described herein,or a microprocessor configured by a computer program that at leastpartially carries out processes and/or devices described herein),electrical circuitry forming a memory device (e.g., forms of randomaccess memory), and/or electrical circuitry forming a communicationsdevice (e.g., a modem, communications switch, or optical-electricalequipment). Those having skill in the art will recognize that thesubject matter described herein may be implemented in an analog ordigital fashion or some combination thereof.

Operation of neural modulation devices as described herein may beperformed under the control of hardware (e.g. analog or digitalelectronic circuitry). Circuitry for switching, signal generation,sensing, timing control etc. is well known and may be constructed bythose of skill in the art of electronics. In some embodiments, controlof neural modulation devices as described herein may be performed undermicroprocessor control. Instructions to be executed by a microprocessormay be stored in hardware, firmware, or software (e.g. as an ASIC,instructions burned into an EEPROM, instructions stored in various typesof memory devices/structures) on various types of signal-bearing media.Instructions for controlling neural modulation devices as describedherein may be used, for example to implement methods as outlined, e.g.in FIGS. 4, 6 and 13-18. Instructions carried on a signal bearing mediummay form a permanent or temporary component of a system includingadditional device components. Signal bearing media used, e.g. asdepicted in FIG. 27, may include both instructions for controllingneural modulation device, and also stored data or parameters. Data,parameters, and instructions may be stored on more than one types ofmedia during the practice of the invention (e.g., partially in devicememory, partially on a removable medium, etc.).

A signal processing portion used in various embodiments as disclosedherein may be configured to perform the various described steps byappropriately configured analog or digital hardware, by instructionsencoded in software or firmware, or combinations thereof, by othermethods as are known to those of skill in the art. Those having skill inthe art will recognize that the state of the art has progressed to thepoint where there is little distinction left between hardware andsoftware implementations of aspects of systems; the use of hardware orsoftware is generally (but not always, in that in certain contexts thechoice between hardware and software can become significant) a designchoice representing cost vs. efficiency tradeoffs. Those having skill inthe art will appreciate that there are various vehicles by whichprocesses and/or systems and/or other technologies described herein canbe effected (e.g., hardware, software, and/or firmware), and that thepreferred vehicle will vary with the context in which the processesand/or systems and/or other technologies are deployed. For example, ifan implementer determines that speed and accuracy are paramount, theimplementer may opt for a mainly hardware and/or firmware vehicle;alternatively, if flexibility is paramount, the implementer may opt fora mainly software implementation; or, yet again alternatively, theimplementer may opt for some combination of hardware, software, and/orfirmware. Hence, there are several possible vehicles by which theprocesses and/or devices and/or other technologies described herein maybe effected, none of which is inherently superior to the other in thatany vehicle to be utilized is a choice dependent upon the context inwhich the vehicle will be deployed and the specific concerns (e.g.,speed, flexibility, or predictability) of the implementer, any of whichmay vary.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, those skilled in the art willrecognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat the mechanisms of the subject matter described herein are capableof being distributed as a program product in a variety of forms, andthat an illustrative embodiment of the subject matter described hereinapplies regardless of the particular type of signal bearing medium usedto actually carry out the distribution. Examples of a signal bearingmedium include, but are not limited to, the following: a recordable typemedium such as a floppy disk, a hard disk drive, a Compact Disc (CD), aDigital Video Disk (DVD), a digital tape, a computer memory, etc.; and atransmission type medium such as a digital and/or an analogcommunication medium (e.g., a fiber optic cable, a waveguide, a wiredcommunications link, a wireless communication link, etc.).

One skilled in the art will recognize that the herein describedcomponents (e.g., steps), devices, and objects and the discussionaccompanying them are used as examples for the sake of conceptualclarity and that various configuration modifications are within theskill of those in the art. Consequently, as used herein, the specificexemplars set forth and the accompanying discussion are intended to berepresentative of their more general classes. In general, use of anyspecific exemplar herein is also intended to be representative of itsclass, and the non-inclusion of such specific components (e.g., steps),devices, and objects herein should not be taken as indicating thatlimitation is desired.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations are not expressly set forth herein for sakeof clarity.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely exemplary, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected”, or“operably coupled”, to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable and/or physically interactingcomponents and/or wirelessly interactable and/or wirelessly interactingcomponents and/or logically interacting and/or logically interactablecomponents.

In some instances, one or more components may be referred to herein as“configured to.” Those skilled in the art will recognize that“configured to” can generally encompass active-state components and/orinactive-state components and/or standby-state components, etc. unlesscontext requires otherwise.

In some instances, one or more components may be referred to herein as“configured to.” Those skilled in the art will recognize that“configured to” can generally encompass active-state components and/orinactive-state components and/or standby-state components, unlesscontext requires otherwise.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to those skilled inthe art that, based upon the teachings herein, changes and modificationsmay be made without departing from the subject matter described hereinand its broader aspects and, therefore, the appended claims are toencompass within their scope all such changes and modifications as arewithin the true spirit and scope of the subject matter described herein.Furthermore, it is to be understood that the invention is defined by theappended claims. It will be understood by those within the art that, ingeneral, terms used herein, and especially in the appended claims (e.g.,bodies of the appended claims) are generally intended as “open” terms(e.g., the term “including” should be interpreted as “including but notlimited to,” the term “having” should be interpreted as “having atleast,” the term “includes” should be interpreted as “includes but isnot limited to,” etc.). It will be further understood by those withinthe art that if a specific number of an introduced claim recitation isintended, such an intent will be explicitly recited in the claim, and inthe absence of such recitation no such intent is present. For example,as an aid to understanding, the following appended claims may containusage of the introductory phrases “at least one” and “one or more” tointroduce claim recitations. However, the use of such phrases should notbe construed to imply that the introduction of a claim recitation by theindefinite articles “a” or “an” limits any particular claim containingsuch introduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

With respect to the appended claims, those skilled in the art willappreciate that recited operations therein may generally be performed inany order. Examples of such alternate orderings may include overlapping,interleaved, interrupted, reordered, incremental, preparatory,supplemental, simultaneous, reverse, or other variant orderings, unlesscontext dictates otherwise. With respect to context, even terms like“responsive to,” “related to,” or other past-tense adjectives aregenerally not intended to exclude such variants, unless context dictatesotherwise.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

1. A method of modulating neural activity comprising the steps of: producing a reversible conduction block in a peripheral neural structure of a subject with a magnetic field blocking stimulus while the subject is in a low activity state; reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state; and repeating the steps of producing a reversible conduction block in a peripheral neural structure of a subject with a magnetic field blocking stimulus while the subject is in a low activity state and reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state.
 2. The method of claim 1, wherein the activity of the subject includes the overall activity of the subject.
 3. The method of claim 1, wherein the activity of the subject includes use of a body portion innervated by the peripheral neural structure by the subject.
 4. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject includes producing a reversible conduction block in a sensory-motor nerve of a subject.
 5. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject includes producing a reversible conduction block in an autonomic nerve of a subject.
 6. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject includes producing a reversible conduction block in a peripheral nerve of a subject.
 7. The method of claim 6, wherein producing a reversible conduction block in a peripheral nerve of a subject includes producing a reversible conduction block in at least one of a radial nerve, a median nerve, an ulnar nerve, a femoral nerve, an obturator nerve, a sciatic nerve, a popliteal nerve, a tibial nerve, a peroneal nerve, or a vagus nerve of a subject.
 8. The method of claim 1, further comprising: receiving an input indicative of an activity state of the subject, wherein the input is indicative of at least one of a low activity state and a higher activity state of the subject.
 9. The method of claim 8, wherein receiving an input indicative of an activity state of the subject includes receiving an input representing physiological activity of the subject.
 10. The method of claim 9, wherein receiving an input representing physiological activity of the subject includes receiving an input representing at least one of heart rate of the subject, respiration, brain activity, peripheral neural activity, muscle activity, or body temperature of the subject.
 11. The method of claim 8, wherein receiving an input indicative of an activity state of the subject includes receiving an input representative of physical activity of the subject.
 12. The method of claim 11, wherein receiving an input representative of physical activity of the subject includes receiving an input representative of at least one of motion, body position, or posture of the subject.
 13. The method of claim 11, wherein receiving an input representative of physical activity of the subject includes receiving an input from at least one of a pressure sensor, a force sensor, an accelerometer, a gyro, a switch, or a piezoelectric device.
 14. The method of claim 8, wherein receiving an input indicative of an activity state of the subject includes receiving an input representing rest or waking state of the subject.
 15. The method of claim 1, including receiving an input indicative of a user instruction.
 16. The method of claim 15, wherein receiving an input indicative of a user instruction includes receiving an input from a user-controlled intermediate device.
 17. The method of claim 15, wherein receiving an input indicative of a user instruction includes receiving a signal from a user input device.
 18. The method of claim 17, wherein receiving a signal from a user input device includes receiving a signal from at least one of a sound-activated input device, a user-activated switch, a pointing device, a touch screen, or a keyboard.
 19. The method of claim 15, wherein receiving an input indicative of a user instruction includes receiving an input indicative of an instruction to modify at least one of the definition of the low activity state or the definition of the higher activity state.
 20. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a first activity state includes producing a reversible conduction block in a peripheral neural structure of a subject with a blocking stimulus source worn on the body of the subject.
 21. The method of claim 20, wherein producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a low activity state includes producing a reversible conduction block in a peripheral neural structure of a subject with a blocking stimulus source located in or on at least one of a wrap adapted to be positioned around at least a portion of the body of the subject, a bracelet configured to be worn on a limb of the subject, an anklet configured to be worn on a limb of the subject, a cuff configured to be worn on a limb of the subject, a collar configured to be worn on a neck of the subject, or necklace configured to be worn on a neck of the subject.
 22. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a low activity state includes producing a reversible conduction block in a peripheral neural structure of a subject with a blocking stimulus source configured to be positioned beneath at least a portion of the body of the subject.
 23. The method of claim 22, wherein producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a low activity state includes producing a reversible conduction block in a peripheral neural structure of a subject with a blocking stimulus source located in or on at least one of a chair, a bed, a pad, or cushion.
 24. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a low activity state includes producing a reversible conduction block in a peripheral neural structure of a subject with a blocking stimulus source implanted within the body of the subject.
 25. The method of claim 1, wherein producing a reversible conduction block includes applying a magnetic field to at least a portion of the peripheral neural structure.
 26. The method of claim 25, wherein producing a reversible conduction block includes applying at least one of a pulsed magnetic field, an oscillating magnetic field, a cyclical magnetic field, a periodic magnetic field, or a time-varying magnetic field to at least a portion of the peripheral neural structure.
 27. The method of claim 1, including reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state by removing the magnetic field blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject.
 28. The method of claim 1, wherein reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state by applying a reversing stimulus configured to counter the magnetic field blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject.
 29. The method of claim 28, wherein applying a reversing stimulus to counter the magnetic field blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject includes applying an electric field to at least a portion of the peripheral neural structure.
 30. The method of claim 28, wherein applying a reversing stimulus to counter the blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject includes applying at least one of a pulsed electric field, a cyclical electric field, or a time-varying electric field to at least a portion of the peripheral neural structure.
 31. The method of claim 28, wherein applying a reversing stimulus to counter the blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject includes applying at least one of a magnetic field, a pulsed magnetic field, or electromagnetic energy to at least a portion of the peripheral neural structure.
 32. The method of claim 28, wherein applying a reversing stimulus to counter the blocking stimulus used to produce the reversible conduction block in the peripheral neural structure of the subject includes at least one of heating or cooling at least a portion of the peripheral neural structure.
 33. The method of claim 1, further comprising: determining that producing the reversible conduction block in the peripheral neural structure of the subject with a magnetic field blocking stimulus while the subject is in a low activity state results in a desired effect in the subject; and producing a non-reversible conduction block in the peripheral neural structure of the subject.
 34. The method of claim 33, including: producing a non-reversible conduction block by applying heat to at least a portion of the peripheral neural structure of the subject.
 35. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject with a magnetic field blocking stimulus while the subject is in a low activity state includes producing a reversible conduction block of a subset of nerve fibers in the peripheral neural structure of the subject with a magnetic field while the subject is in the low activity state; reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state includes reversing the reversible conduction block of the subset of nerve fibers in the peripheral neural structure of the subject to permit conduction in the subset of nerve fibers in the peripheral neural structure when the subject is in the higher activity state.
 36. The method of claim 35, wherein the subset of nerve fibers in the peripheral neural structure of the subject includes at least one of nerve fibers within a selected diameter range, nerve fibers within a selected spatial distribution within the peripheral neural structure, nerve fibers within selected fascicles within the peripheral neural structure, or nerve fibers including a selected molecular feature.
 37. The method of claim 33, including: producing a non-reversible conduction block by removing heat from at least a portion of the peripheral neural structure of the subject.
 38. The method of claim 33, wherein producing a non-reversible conduction block includes producing substantially complete blockage of conduction in the peripheral neural structure of the subject.
 39. The method of claim 33, including: producing a non-reversible conduction block by at least one of applying an electrical current to at least a portion of the peripheral neural structure of the subject, delivering acoustic energy to at least a portion of the peripheral neural structure of the subject, delivering photons to at least a portion of the peripheral neural structure of the subject, delivering a chemical agent to at least a portion of the peripheral neural structure of the subject, or surgical transection of at least a portion of the peripheral neural structure of the subject.
 40. The method of claim 1, wherein the steps of producing a reversible conduction block in a peripheral neural structure of a subject while the subject is in a low activity state and reversing the reversible conduction block in the peripheral neural structure of the subject to permit conduction in the peripheral neural structure when the subject is in a higher activity state occur over a period of time sufficient to produce a modulation of at least one of an immune response an inflammatory response in a region innervated by the peripheral neural structure.
 41. The method of claim 1, wherein producing a reversible conduction block in a peripheral neural structure of a subject includes producing a reversible conduction block in at least one of a spinal root, a geniculate ganglion, an autonomic ganglion, or a nerve plexus of a subject.
 42. The method of claim 1, including at least one of storing information regarding an activity state of the subject, storing information regarding producing the reversible conduction block, transmitting information regarding an activity state of the subject, or transmitting information regarding producing the reversible conduction block. 